Sustained delivery formulations of risperidone compounds

ABSTRACT

The present invention relates to a risperidone sustained release delivery system for treatment of medical conditions relating delusional psychosis, schizophrenia, bipolar disorder, psychotic depression, obsessive-compulsion disorder, Tourette syndrome, and autistic spectrum disorders. The sustained release delivery system includes a flowable composition containing risperidone, a metabolite, or a prodrug thereof and an implant containing risperidone, a metabolite, or a prodrug thereof. The flowable composition may be injected into tissue whereupon it coagulates to become the solid or gel, monolithic implant. The flowable composition includes a biodegradable, thermoplastic polymer, an organic liquid, and risperidone, a metabolite, or a prodrug thereof.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/602,058, filed Jun. 30, 2010, which is a U.S. National-Stage entryunder 35 U.S.C. §371 based on International Application No.PCT/US2008/001928, filed 13 Feb. 2008, and published in English as WO2008/153611 A2 on 18 Dec. 2008, which designates the United States ofAmerica, and claims priority under 35 U.S.C. §119(e) to U.S. ApplicationSer. No. 60/940,340, filed May 25, 2007, each of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

This disclosure relates to a risperidone sustained release deliverysystem for treatment of diseases ameliorated by risperidone compounds.The sustained release delivery system includes a flowable compositioncontaining risperidone, a metabolite, or a prodrug thereof and animplant containing risperidone, a metabolite, or a prodrug thereof.

BACKGROUND OF THE INVENTION

Risperidone (also known as4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-oneand marketed under the trade name RISPERDAL®) is an atypicalantipsychotic medication. The chemical structure of risperidone is shownin formula (1).

Risperidone is most often used to treat delusional psychosis (includingschizophrenia), but risperidone is also used to treat some forms ofbipolar disorder, psychotic depression, obsessive-compulsion disorder,and Tourette syndrome. Risperidone is also used in low doses fortreating autistic spectrum disorders. Risperidone's therapeutic activityin schizophrenia is believed to be mediated through a combination ofdopamine Type 2 (D₂) and serotonin Type 2 (5HT₂) receptor antagonism.

Currently, the commercial sustained-release product of an atypicalpsychotic is RISPERDAL® CONSTA® marketed by Janssen, L.P. RISPERDAL®CONSTA® is an intramuscular microsphere formulation and is intended todeliver therapeutic levels of risperidone for two weeks. However, due tothe inherent lag phase of most microsphere products, the patient isrequired to supplement the first 21 days of RISPERDAL® CONSTA® treatmentwith daily doses of risperidone. Approximately three weeks after asingle intramuscular injection of RISPERDAL® CONSTA® and concurrentdaily doses of oral risperidone, the microspheres release sufficientrisperidone in the systemic circulation that the patient can discontinuesupplementation with daily doses of the oral therapy.

The primary limitation of liposomes and microspheres used insustained-release delivery systems is, typically, the limited amount ofdrug that can be entrapped in the dosage form. The amount of spaceavailable to entrap drug is restricted by the structure of theparticulate. Further, the size of the injection is limited by thediscomfort of the patient.

Other sustained-release delivery systems such as solid, biodegradablerods, or nondegradable reservoirs typically require surgicalimplantation. Furthermore, for the nondegradable delivery systems, asecond surgical procedure is required to remove the empty reservoir.

There is a continuing need to develop products providing increasedbioavailability of risperidone. In particular, there is a need todevelop sustained release formulations of risperidone that do not sufferfrom low bioavailability, poor release kinetics, injection sitetoxicity, relatively large volume injections, and inconveniently shortduration of release.

SUMMARY OF THE INVENTION

The present invention is directed to a risperidone sustained releasedelivery system capable of delivering risperidone, a metabolite, or aprodrug thereof for a duration of about 14 days to about 3 months. Therisperidone sustained release delivery system includes a flowablecomposition and a gel or solid implant for the sustained release ofrisperidone, a metabolite, or a prodrug thereof. The implant is producedfrom the flowable composition. The risperidone sustained releasedelivery system provides in situ 1-month and 3-month release profilescharacterized by an exceptionally high bioavailability and minimal riskof permanent tissue damage and typically no risk of muscle necrosis.

Several direct comparisons between the risperidone sustained releasedelivery system and RISPERDAL® CONSTA® have been conducted. In addition,the sustained release delivery system provides blood levels in thetherapeutic range immediately after injection, whereas RISPERDAL®CONSTA® product has exhibited the characteristic lag phase prior to therelease of risperidone.

In one embodiment, a risperidone sustained release delivery system isprovided. This delivery system includes a flowable composition and acontrolled, sustained release implant. The flowable composition includesa biodegradable thermoplastic polymer, a biocompatible, polar, aproticorganic liquid, and risperidone, a metabolite, or a prodrug thereof. Theflowable composition may be transformed into the implant by contact withwater, body fluid, or other aqueous medium. In one embodiment, theflowable composition is injected into the body whereupon it transformsin situ into the solid or gel implant.

The thermoplastic polymer of the flowable composition and implant is atleast substantially insoluble in an aqueous medium or body fluid, ortypically completely insoluble in those media. The thermoplastic polymermay be a homopolymer, a copolymer, or a terpolymer of repeatingmonomeric units linked by such groups as ester groups, anhydride groups,carbonate groups, amide groups, urethane groups, urea groups, ethergroups, esteramide groups, acetal groups, ketal groups, orthocarbonategroups, and any other organic functional group that can be hydrolyzed byenzymatic or hydrolytic reaction (i.e., is biodegradable by thishydrolytic action). The thermoplastic polymer may be a polyester thatmay be composed of units of about one or more hydroxycarboxylic acidresidues, or diol and dicarboxylic acid residues, wherein thedistribution of differing residues may be random, block, paired, orsequential. The polyester may be a combination of about one or morediols and about one or more dicarboxylic acids. The hydroxy carboxylicacid or acids may also be in the form of dimers.

When the biodegradable thermoplastic polymer is a polyester, thepolyesters include, for example, a polylactide, a polyglycolide, apolycaprolactone, a copolymer thereof, a terpolymer thereof, or anycombination thereof, optionally incorporating a third mono-alcohol orpolyol component. More preferably, the biodegradable thermoplasticpolyester is a polylactide, a polyglycolide, a copolymer thereof, aterpolymer thereof, or a combination thereof, optionally incorporating athird mono-alcohol or polyol component. More preferably, the suitablebiodegradable thermoplastic polyester is about 50/50poly(lactide-co-glycolide) (hereinafter PLG) having a carboxy terminalgroup or is a 75/25 or a 85/15 PLG with a carboxy terminal group or sucha PLG formulated with about one or more mono-alcohol or polyol units.When a mono-alcohol or polyol is incorporated into the polyester, themono-alcohol or polyol constitutes a third covalent component of thepolymer chain. When a mono-alcohol is incorporated, the carboxy terminusof the polyester is esterified with the mono-alcohol. When a polyol isincorporated, it chain extends and optionally branches the polyester.The polyol functions as a polyester polymerization point with thepolyester chains extending from multiple hydroxyl moieties of thepolyol, and those hydroxyl moieties are esterified by a carboxyl groupof the polyester chain. For an embodiment employing a diol, thepolyester is linear with polyester chains extending from both esterifiedhydroxy groups. For an embodiment employing a triol or higher polyol,the polyester may be linear or may be branched with polyester chainsextending from the esterified hydroxy groups. Suitable polyols include,for example, aliphatic and aromatic diols, saccharides such as glucose,lactose, maltose, sorbitol, triols such as glycerol, fatty alcohols, andthe like, tetraols, pentaols, hexaols, and the like.

The biodegradable thermoplastic polymer can be present in any suitableamount, provided the biodegradable thermoplastic polymer is at leastsubstantially insoluble in aqueous medium or body fluid. Thebiodegradable thermoplastic polymer is present in about 10 wt. % toabout 95 wt. % of the flowable composition, preferably present in about20 wt. % to about 70 wt. % of the flowable composition or morepreferably is present in about 30 wt. % to about 60 wt. % of theflowable composition. Preferably, the biodegradable thermoplasticpolymer has an average molecular weight of about 10,000 Daltons (Da) toabout 45,000 Daltons, or more preferably about 15,000 Daltons to about40,000 Daltons.

The biodegradable thermoplastic polymer may also be a non-hydrolyzed PLGlow-burst copolymer polyester material having a weight average molecularweight of about 10 kilodaltons (kDa) to about 50 kilodaltons, apolydispersity index of about 1.4 to about 2.0, and from which acopolymer fraction characterized by a weight average molecular weight ofabout 4 kDa to about 10 kDa and a polydispersity index of about 1.4 toabout 2.5 has been removed.

The flowable composition also includes a biocompatible, polar aproticorganic liquid. The biocompatible polar aprotic liquid can be an amide,an ester, a carbonate, a ketone, an ether, a sulfonyl, or any otherorganic compound that is liquid at ambient temperature, is polar and isaprotic. The biocompatible polar aprotic organic liquid may be veryslightly soluble to completely soluble in all proportions in body fluid.While the organic liquid generally should have similar solubilityprofiles in aqueous medium and body fluid, body fluid is typically morelipophilic than aqueous medium. Consequently, some organic liquids thatare insoluble in aqueous medium should be at least slightly soluble inbody fluid. These examples of organic liquid are included within thedefinition of organic liquids.

Preferably, the biocompatible polar aprotic liquid comprisesN-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, or anycombination thereof. More preferably, the biocompatible polar aproticliquid is N-methyl-2-pyrrolidone. Preferably, the polar aprotic organicliquid is present in about 10 wt. % to about 90 wt. % of the compositionor is present in about 30 wt. % to about 70 wt. % of the composition.

The risperidone, a metabolite, or a prodrug thereof is present in atleast about 0.001 wt. % concentration in the flowable composition withthe upper limit being the limit of dispersibility of the risperidone, ametabolite, or a prodrug thereof within the flowable composition.Preferably, the concentration is about 0.5 wt. % to about 50 wt. % ofthe flowable composition or more preferably about 1 wt. % to about 30wt. % of the flowable composition.

The risperidone, a metabolite, or a prodrug thereof in the flowablecomposition may be in the form of a salt and the salt gegenion may bederived from a pharmaceutically acceptable organic or inorganic acid, orpreferably the gegenion may be a polycarboxylic acid.

Preferably, the flowable composition is formulated as an injectabledelivery system. The flowable composition preferably has a volume ofabout 0.20 mL to about 2.0 mL or preferably about 0.30 mL to about 1.0mL. The injectable composition is preferably formulated foradministration about once per month, about once per three months, orabout once per four months, to about once per six months. Preferably,the flowable composition is a liquid or a gel composition, suitable forinjection into a patient. The flowable composition may have the propertyof production of minimal tissue necrosis when injected subcutaneously.

Excipients, release modifiers, plasticizers, pore forming agents,gelation liquids, non-active extenders, and other ingredients may alsobe included within the risperidone sustained release delivery system.Upon administration of the flowable composition, some of theseadditional ingredients, such as gelation liquids and release modifiersshould remain with the implant, while others, such as pore formingagents should separately disperse and/or diffuse along with the organicliquid.

In one embodiment, a method is provided for forming a flowablecomposition for use as a controlled release implant. The method includesmixing, in any order, a biodegradable thermoplastic polymer, abiocompatible polar aprotic liquid, and risperidone, a metabolite, or aprodrug thereof. The biodegradable thermoplastic polymer may be at leastsubstantially insoluble in aqueous medium or body fluid. Theseingredients, their properties, and preferred amounts are as disclosedabove. The mixing is performed for a sufficient period of time effectiveto form the flowable composition for use as a controlled releaseimplant. Preferably, the biocompatible thermoplastic polymer and thebiocompatible polar aprotic organic liquid are mixed together to form amixture and the mixture is combined with the risperidone, a metabolite,or a prodrug thereof to form the flowable composition. Preferably, theflowable composition is a solution or dispersion, especially preferablya solution, of the risperidone, a metabolite, or a prodrug thereof andbiodegradable thermoplastic polymer in the organic liquid. The flowablecomposition preferably includes an effective amount of a biodegradablethermoplastic polymer, an effective amount of a biocompatible polaraprotic organic liquid, and an effective amount of risperidone, ametabolite, or a prodrug thereof. These ingredients, the preferredingredients, their properties, and preferred amounts are as disclosedabove.

In one embodiment, a biodegradable implant formed in situ, in a patientis provided, by the steps including: injecting a flowable compositionincluding a biodegradable thermoplastic polymer that is at leastsubstantially insoluble in body fluid, a biocompatible polar aproticorganic liquid; and risperidone, a metabolite, or a prodrug thereof intothe body of the patient, and allowing the biocompatible polar aproticliquid to dissipate to produce a solid or gel biodegradable implant. Theflowable composition includes an effective amount of the biodegradablethermoplastic polymer, an effective amount of the biocompatible polaraprotic liquid, and an effective amount of risperidone, a metabolite, ora prodrug thereof and the solid implant releases an effective amount ofrisperidone, a metabolite, or a prodrug thereof over time as the solidimplant biodegrades in the patient and optionally the patient is ahuman.

In one embodiment, a method is provided of forming a biodegradableimplant in situ, in a living patient. The method includes injecting theflowable composition including a biodegradable thermoplastic polymerthat is at least substantially insoluble in body fluid, a biocompatiblepolar aprotic organic liquid, and risperidone, a metabolite, or aprodrug thereof within the body of a patient and allowing thebiocompatible polar aprotic organic liquid to dissipate to produce asolid or gel biodegradable implant. Preferably, the biodegradable solidor gel implant releases an effective amount of risperidone, ametabolite, or a prodrug thereof by diffusion, erosion, or a combinationof diffusion and erosion as the solid or gel implant biodegrades in thepatient.

In one embodiment, a method is provided of treating or preventingmammalian diseases that are ameliorated, cured, or prevented byrisperidone, a metabolite, or a prodrug thereof. The method includesadministering, to a patient (preferably a human patient) in need of suchtreatment or prevention, an effective amount of a flowable compositionincluding a biodegradable thermoplastic polymer that is at leastsubstantially insoluble in body fluid, a biocompatible polar aproticorganic liquid, and risperidone, a metabolite, or a prodrug thereof.

In one embodiment, a kit is provided. The kit includes a first containerand a second container. The first container includes a composition ofthe biodegradable thermoplastic polymer and the biocompatible polaraprotic organic liquid. The biodegradable thermoplastic polymer may beat least substantially insoluble in aqueous medium or body fluid. Thesecond container includes risperidone, a metabolite, or a prodrugthereof. These ingredients, their properties, and preferred amounts areas disclosed above. Preferably, the first container is a syringe and thesecond container is a syringe. In addition, the risperidone, ametabolite, or a prodrug thereof may be lyophilized. The kit canpreferably include, for example, instructions. Preferably, the firstcontainer can be connected to the second container. More preferably, thefirst container and the second container are each configured to bedirectly connected to each other.

In one embodiment, a solid or gel implant is provided. The solid or gelimplant is composed of at least the biocompatible thermoplastic polymerand risperidone, a metabolite, or a prodrug thereof and is substantiallyinsoluble in body fluid. The biodegradable thermoplastic polymer may beat least substantially insoluble in aqueous medium or body fluid. Whilerisperidone, a metabolite, or a prodrug thereof itself has at least somesolubility in body fluid, its isolation within the substantiallyinsoluble implant allows for its slow, sustained release into the body.

The solid implant has a solid matrix or a solid microporous matrix whilethe gel implant has a gelatinous matrix. The matrix can be a coresurrounded by a skin. The implant may be solid and microporous. Whenmicroporous, the core preferably contains pores of diameters from about1 to about 1000 microns. When microporous, the skin preferably containspores of smaller diameters than those of the core pores. In addition,the skin pores are preferably of a size such that the skin isfunctionally non-porous in comparison with the core.

The solid or gel implant can optionally include, for example, one ormore biocompatible organic substances which may function as an excipientas described above, or which may function as a plasticizer, a sustainedrelease profile modifier, emulsifier, and/or isolation carrier forrisperidone, a metabolite, or a prodrug thereof.

The biocompatible organic liquid may also serve as an organic substanceof the implant and/or may provide an additional function such as aplasticizer, a modifier, an emulsifier, or an isolation carrier. Theremay be two or more organic liquids present in the flowable compositionsuch that the primary organic liquid acts as a mixing, solubilizing, ordispersing agent, and the supplemental organic liquid or liquids provideadditional functions within the flowable composition and the implant.Alternatively, there may be one organic liquid which at least may act asa mixing, solubilizing, or dispersing agent for the other components,and may provide additional functions as well. As second or additionalcomponents, additional kinds of biodegradable organic liquids typicallyare combined with the flowable composition and may remain with theimplant as the administered flowable composition coagulates.

When serving as a plasticizer, the biocompatible organic substanceprovides such properties as flexibility, softness, moldability, and drugrelease variation to the implant. When serving as a modifier, thebiocompatible organic substance also provides the property ofrisperidone release variation to the implant. Typically, the plasticizerincreases the rate of risperidone, a metabolite, or a prodrug thereofrelease while the modifier slows the rate of risperidone, a metabolite,or a prodrug thereof release. Also, there can be structural overlapbetween these two kinds of organic substances functioning asplasticizers and rate modifiers.

When serving as an emulsifier, the biocompatible organic substance atleast in part enables a uniform mixture of the risperidone, ametabolite, or a prodrug thereof within the flowable composition andwithin the implant.

When serving as an isolation carrier, the biocompatible organicsubstance should function to encapsulate, isolate, or otherwise surroundmolecules or nanoparticles of the risperidone, a metabolite, or aprodrug thereof so as to prevent its burst at least in part, and toisolate the risperidone, a metabolite, or a prodrug thereof fromdegradation by other components of the flowable composition and implant.

The amount of biocompatible organic substance optionally remaining inthe solid or gel implant is preferably minor, such as from about 0 wt. %(or an almost negligible amount) to about 20 wt. % of the composition.In addition, the amount of biocompatible organic substance optionallypresent in the solid or gel implant preferably decreases over time.

The solid implant may also include, for example, a biocompatible organicliquid that is very slightly soluble to completely soluble in allproportions in body fluid and at least partially dissolves at least aportion of the thermoplastic polyester, and optionally the amount ofbiocompatible organic liquid is less than about 5 wt. % of the totalweight of the implant, and optionally the amount of biocompatibleorganic liquid decreases over time.

The solid implant may also include, for example, a core that containspores of diameters from about 1 to about 1000 microns, and optionallythe skin contains pores of smaller diameters than those of the corepores, and optionally the skin pores are of a size such that the skin isfunctionally non-porous in comparison with the core.

In one embodiment, a flowable composition having a substantially linearcumulative release profile is provided.

In one embodiment, a method is provided for treatment of a patienthaving a medical condition including administering to the patient aneffective amount of risperidone, a metabolite, or a prodrug thereof incombination with an at least substantially water-insoluble biodegradablethermoplastic polymer and a biocompatible, polar, aprotic organicliquid, wherein the mental condition comprises delusional psychosis,schizophrenia, bipolar disorder, psychotic depression,obsessive-compulsion disorder, Tourette syndrome, autistic spectrumdisorders, or any combination thereof. This method of treatment mayinclude, for example, combination therapy with another knownpharmaceutical compound designated for treatment of the malcondition.

In one embodiment, a method is provided for treating a patient having amedical condition comprising administering to the patient a flowablecomposition to provide a biodegradable implant comprising risperidone, ametabolite, or a prodrug thereof and a biodegradable polymer, whereinthe implant releases delivers therapeutically effective dosage fromabout 1 to about 16 milligrams (mg) of risperidone, a metabolite, or aprodrug thereof per day, or preferably from about 1 to about 5milligrams (mg) of risperidone, a metabolite, or a prodrug thereof perday.

The therapeutically effective dosage of risperidone, a metabolite, or aprodrug thereof may be achieved within about two days afteradministration of the implant, or preferably, within about one day afteradministration of the implant.

The therapeutically effective dosage of risperidone, a metabolite, or aprodrug thereof may be delivered for at least about 15 days afteradministration of the implant, or preferably for at least about 30 daysafter administration of the implant, or preferably for at least about 45days after administration of the implant, or preferably for at leastabout 60 days after administration of the implant.

The medical condition may include, for example, delusional psychosis,schizophrenia, bipolar disorder, psychotic depression,obsessive-compulsion disorder, Tourette syndrome, and autistic spectrumdisorders. The individual may be a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the 24-hour release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 2 illustrates the 24-hour release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 3 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 4 illustrates the 28-day plasma concentration of active risperidonein rats.

FIG. 5 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 6 illustrates the 28-day plasma concentration of active risperidonein rats.

FIG. 7 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 8 illustrates the 28-day plasma concentration of active risperidonein rats.

FIG. 9 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 10 illustrates the 28-day plasma concentration of activerisperidone in rats.

FIG. 11 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 12 illustrates the 28-day plasma concentration of activerisperidone in rats.

FIG. 13 illustrates the 28-day release of risperidone from selectedATRIGEL® formulations in rats.

FIG. 14 illustrates the 28-day plasma concentration of activerisperidone in rats.

FIG. 15 illustrates the 50-day risperidone/ATRIGEL® pharmacokineticstudy in rabbits.

FIG. 16 illustrates the 35-day risperidone/ATRIGEL® pharmacokineticstudy in rabbits.

FIG. 17 illustrates the 45-day risperidone/ATRIGEL® pharmacokineticstudy in dogs.

FIG. 18 illustrates the 45-day risperidone/ATRIGEL® pharmacokineticstudy in dogs.

FIG. 19 illustrates the pharmacokinetics of RISPERDAL® tablet daily oraldoses of 2 mg, 3 mg, and 4 mg in dogs.

FIG. 20 illustrates the pharmacokinetics of risperidone/ATRIGEL®formulation after subcutaneous into dogs with 60 mg, 90 mg, and 120 mgdoses.

FIG. 21 illustrates the pharmacokinetics comparison between 60 mgrisperidone/ATRIGEL® formulation injected subcutaneous into dogs and 2mg RISPERDAL® tablet daily oral dose.

FIG. 22 illustrates the pharmacokinetics comparison between 90 mgrisperidone/ATRIGEL® formulation injected subcutaneous into dogs and 3mg RISPERDAL® tablet daily oral dose.

FIG. 23 illustrates the pharmacokinetics comparison between 120 mgrisperidone/ATRIGEL® formulation injected subcutaneous into dogs and 4mg RISPERDAL® tablet daily oral dose.

FIG. 24 illustrates the pharmacokinetics on day 0 and day 30 of 2 mg, 3mg, and 4 mg RISPERDAL® tablet daily oral dose groups.

FIG. 25 illustrates the plasma levels of risperidone and the relatedpharmacological response ofrisperidone/poly(DL-lactide-co-caprolactone)/ethyl lactate in dogs.

FIG. 26 illustrates the plasma levels of risperidone and the relatedpharmacological response ofrisperidone/poly(DL-lactide-co-glycolide)/ethyl lactate in dogs.

FIG. 27 illustrates the plasma levels of risperidone and the relatedpharmacological response ofrisperidone/poly(DL-lactide-co-caprolactone)/N-methyl-2-pyrrolidone indogs.

FIG. 28 illustrates the plasma levels of risperidone and the relatedpharmacological response ofrisperidone/poly(DL-lactide-co-glycolide)/N-methyl-2-pyrrolidone indogs.

DEFINITIONS

The words and phrases presented in this patent application have theirordinary meanings to one of skill in the art unless otherwise indicated.Such ordinary meanings can be obtained by reference to their use in theart and by reference to general and scientific dictionaries such asWEBSTER'S NEW WORLD DICTIONARY, Simon & Schuster, New York, N.Y., 1995,THE AMERICAN HERITAGE DICTIONARY OF THE ENGLISH LANGUAGE, HoughtonMifflin, Boston Mass., 1981, and HAWLEY'S CONDENSED CHEMICAL DICTIONARY,14^(th) edition, Wiley Europe, 2002.

The following explanations of certain terms are meant to be illustrativerather than exhaustive. These terms have their ordinary meanings givenby usage in the art and in addition include the following explanations.

As used herein, the term “and/or” means any one of the items, anycombination of the items, or all of the items with which this term isassociated.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly dictates otherwise. Thus, forexample, a reference to “a formulation” includes a plurality of suchformulations, so that a formulation of compound X includes formulationsof compound X.

As used herein, the term “acceptable salts” refer to derivatives whereinthe parent compound is modified by making acid or base salts thereof.Suitable acceptable salts include, but are not limited to, mineral ororganic acid salts of basic residues such as amines; alkali or organicsalts of acidic residues such as carboxylic acids; and the like. Theacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric, and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. Specifically, the acceptable salts can include, forexample, those salts that naturally occur in vivo in a mammal.

As used herein, the term “biocompatible” means that the material,substance, compound, molecule, polymer, or system to which it appliesshould not cause severe toxicity, severe adverse biological reaction, orlethality in an animal to which it is administered at reasonable dosesand rates.

As used herein, the term “biodegradable” means that the material,substance, compound, molecule, polymer, or system is cleaved, oxidized,hydrolyzed, or otherwise broken down by hydrolytic, enzymatic, oranother mammalian biological process for metabolism to chemical unitsthat can be assimilated or eliminated by the mammalian body.

As used herein, the term “bioerodible” means that the material,substance, compound, molecule, polymer, or system is biodegraded ormechanically removed by a mammalian biological process so that newsurface is exposed.

As used herein, the term “therapeutically effective amount” is intendedto include an amount of risperidone, a metabolite, or a prodrug thereof,a pharmaceutically acceptable salt thereof, a derivative thereof, or anycombination of those useful to treat or prevent the underlying disorderor disease, or to treat the symptoms associated with the underlyingdisorder or disease in a host. Synergy, as described, for example, byChou and Talalay, Adv. Enzyme Regul. 22, 27-55 (1984), occurs when theeffect of risperidone, a metabolite, or a prodrug thereof, apharmaceutically acceptable salt thereof, or a derivative thereof whenadministered in combination is greater than the additive effect of therisperidone, a metabolite, or a prodrug thereof, pharmaceuticallyacceptable salt thereof, or a derivative thereof when administered aloneas a single agent. In general, a synergistic effect is most clearlydemonstrated at suboptimal concentrations of the risperidone, ametabolite, or a prodrug thereof, a pharmaceutically acceptable saltthereof, or derivative thereof. Synergy can be in terms of lowercytotoxicity, increased activity, or some other beneficial effect of thecombination compared with the individual components.

As used herein, the term “flowable” refers to the ability of the“flowable” composition to be transported under pressure into the body ofa patient. For example, the flowable composition can have a lowviscosity like water, and be injected with the use of a syringe, beneaththe skin of a patient. The flowable composition can alternatively have ahigh viscosity as in a gel and can be placed into a patient through ahigh pressure transport device such as a high pressure syringe, cannula,needle, and the like. The ability of the composition to be injected intoa patient should typically depend upon the viscosity of the composition.The composition should therefore have a suitable viscosity ranging fromlow like water to high like a gel, such that the composition can beforced through the transport device (e.g., syringe) into the body of apatient.

As used herein, the term “gel” refers to a substance having agelatinous, jelly-like, or colloidal properties. See, e.g., CONCISECHEMICAL AND TECHNICAL DICTIONARY, 4^(th) Edition, Chemical PublishingCo., Inc., p. 567, New York, N.Y. (1986).

As used herein, the term “liquid” refers to a substance that undergoescontinuous deformation under a shearing stress. See, e.g., CONCISECHEMICAL AND TECHNICAL DICTIONARY, 4^(th) Edition, Chemical PublishingCo., Inc., p. 707, New York, N.Y. (1986).

As used herein, the term “patient” refers to a warm-blooded animal, andpreferably a mammal, such as, for example, a cat, dog, horse, cow, pig,mouse, rat, or primate, including a human.

As used herein, the term “polymer” refers to a molecule of one or morerepeating monomeric residue units covalently bonded together by one ormore repeating chemical functional groups. The term includes allpolymeric forms such as linear, branched, star, random, block, graft,and the like. It includes homopolymers formed from a single monomer,copolymer formed from two or more monomers, terpolymers formed fromthree or more polymers, and polymers formed from more than threemonomers. Differing forms of a polymer may also have more than onerepeating, covalently bonded functional group. The term may also referto substantially linear polyesters, also referred to herein as “PLGcopolymers,” predominantly formed of monomeric lactate and glycolatehydroxyacids, or lactide and glycolide dimeric hydroxyacids, andinclude, for example, compositions referred to in the art aspoly(lactate-glycolate), poly(lactate(co)glycolate),poly(lactide-glycolide), poly(lactide (co)glycolide), PLG, PLGH, and thelike, with the understanding that additional moieties may be included,such as core/initiator groups (for example, diols, hydroxyacids, and thelike), capping groups (for example, esters of terminal carboxyl groups,and the like) and other pendant groups or chain extension groupscovalently linked to or within a polyester backbone, including groupsthat cross-link the substantially linear polyester molecular chains,without departing from the meaning assigned herein. PLG copolymers, asthe term is used herein, includes molecular chains with terminalhydroxyl groups, terminal carboxyl groups (i.e., acid-terminated,sometimes termed PLGH) and terminal ester groups (i.e., capped).

As used herein, the term “polyester” refers to polymers containingmonomeric repeats, at least in part, of the linking group: —OC(═O)— or—C(═O)O—.

As used herein, the terms “skin” and “core” of a skin and core matrixmean that a cross section of the matrix should present a discernabledelineation between an outer surface and the inner portion of thematrix. The outer surface is the skin and the inner portion is the core.

As used herein, the term “thermoplastic” as applied to a polymer meansthat the polymer repeatedly should melt upon heating and should solidifyupon cooling. It signifies that no or a slight degree of cross-linkingbetween polymer molecules is present. It is to be contrasted with theterm “thermoset” which indicates that the polymer should set orsubstantially cross-link upon heating or upon application of a similarreactive process and should no longer undergo melt-solidification cyclesupon heating and cooling.

As used herein, the terms “treating,” “treat,” or “treatment” includes(i) preventing a pathologic condition (e.g., schizophrenia) fromoccurring (e.g., prophylaxis); (ii) inhibiting the pathologic condition(e.g., schizophrenia) or arresting its development; and (iii) relievingthe pathologic condition (e.g., relieving the symptoms associated withschizophrenia).

DESCRIPTION OF THE INVENTION

The present invention is directed to a risperidone sustained releasedelivery system. The sustained release delivery system includes aflowable composition and a gel or solid implant. The delivery systemprovides an in situ sustained release of risperidone, a metabolite, or aprodrug thereof. The flowable composition accomplishes the sustainedrelease through its use to produce the implant. The implant has a lowimplant volume and provides a long term delivery of risperidone, ametabolite, or a prodrug thereof. The flowable composition enablessubcutaneous formation of the implant in situ and causes little or notissue necrosis. The in situ implant exhibits superior results relativeto the RISPERDAL® CONSTA® product in that the implant delivers higherand longer lasting blood levels of the risperidone compared with theRISPERDAL® CONSTA® product. The in situ implant provides therapeuticplasma risperidone, a metabolite, or a prodrug thereof levelsimmediately after injection and maintains steady-state plasma levelsfrom four to six weeks. Further, the in situ implant does not requiresupplemental daily oral doses of RISPERDAL® for the first twenty-onedays, as required with the RISPERDAL® CONSTA® product.

Another advantage is that the in situ implant should provide greaterpatience compliance. RISPERDAL® CONSTA® is administered as a 2.0 mLintramuscular injection, whereas one embodiment is injected into thesubcutaneous space with a volume of injection of about 0.80 mL. It ispostulated that patients should prefer a smaller subcutaneous injection(bout 0.80 mL) over a larger (about 2.0 mL) intramuscular injection.

Another advantage of one embodiment includes a simple manufacturingprocess and delivery system. For example, the risperidone, a metabolite,or a prodrug thereof is filled into a syringe, the syringe is sealed,and the entire drug substance syringe is terminally sterilized by gammairradiation. The biodegradable polymer used is dissolved inN-methyl-2-pyrrolidinone and filled in a second syringe. The syringe issealed and the delivery system is terminally sterilized by gammairradiation. At the time of injection, the syringes are coupled throughthe luer-lock connection and the product is constituted by cycling thecomponents between the two syringes. In this way, the drug isincorporated into the delivery system and very little is lost to thedevice.

In contrast, the RISPERDAL® CONSTA® product is made by a microsphereformation and encapsulation process, before being injected into thepatient.

The flowable composition is a combination of a biodegradable, at leastsubstantially water-insoluble thermoplastic polymer, a biocompatiblepolar aprotic organic liquid and risperidone, a metabolite, or a prodrugthereof. The polar, aprotic organic liquid has a solubility in bodyfluid ranging from practically insoluble to completely soluble in allproportions. Preferably, the thermoplastic polymer is a thermoplasticpolyester of about one or more hydroxycarboxylic acids or about one ormore diols and dicarboxylic acids. Especially preferably, thethermoplastic polymer is a polyester of about one or morehydroxylcarboxyl dimers such as lactide, glycolide, dicaprolactone, andthe like.

The specific and preferred biodegradable thermoplastic polymers andpolar aprotic solvents; the concentrations of thermoplastic polymers,polar aprotic organic liquids, and risperidone, a metabolite, or aprodrug thereof; the molecular weights of the thermoplastic polymer; andthe weight or mole ranges of components of the solid implant describedherein are exemplary. They do not exclude other biodegradablethermoplastic polymers and polar aprotic organic liquids; otherconcentrations of thermoplastic polymers, polar aprotic liquids, andrisperidone, a metabolite, or a prodrug thereof; other molecular weightsof the thermoplastic polymer; and other components within the solidimplant.

In one embodiment, a flowable composition suitable for use in providinga controlled sustained release implant is provided, a method for formingthe flowable composition, a method for using the flowable composition,the biodegradable sustained release solid or gel implant that is formedfrom the flowable composition, a method of forming the biodegradableimplant in situ, a method for treating disease through use of thebiodegradable implant and a kit that includes the flowable composition.The flowable composition may preferably be used to provide abiodegradable or bioerodible microporous in situ formed implant inanimals.

The flowable composition is composed of a biodegradable thermoplasticpolymer in combination with a biocompatible polar aprotic organic liquidand risperidone, a metabolite, or a prodrug thereof. The biodegradablethermoplastic polymer is substantially insoluble in aqueous mediumand/or in body fluid, biocompatible, and biodegradable and/orbioerodible within the body of a patient. The flowable composition maybe administered as a liquid or gel into tissue and forms an implant insitu. Alternatively, the implant may be formed ex vivo by combining theflowable composition with an aqueous medium. In this embodiment, thepreformed implant may be surgically administered to the patient. Ineither embodiment, the thermoplastic polymer coagulates or solidifies toform the solid or gel implant upon the dissipation, dispersement, orleaching of the organic liquid from the flowable composition when theflowable composition contacts a body fluid, an aqueous medium, or water.The coagulation or solidification entangles and entraps the othercomponents of the flowable composition such as risperidone, ametabolite, or a prodrug thereof excipients, organic substances, and thelike, so that they become dispersed within the gelled or solidifiedimplant matrix. The flowable composition is biocompatible and thepolymer matrix of the implant does not cause substantial tissueirritation or necrosis at the implant site. The implant delivers asustained level of risperidone, a metabolite, or a prodrug thereof tothe patient. Preferably, the flowable composition can be a liquid or agel, suitable for injection in a patient (e.g., human).

One embodiment surprisingly improves the bioavailability of a sustainedrelease formulation of risperidone, a metabolite, or a prodrug thereof.In addition, one embodiment provides: (a) relatively low volumeinjections; (b) improved local tissue tolerance at the injection site;(c) an opportunity to use a subcutaneous injection rather than anintramuscular injection; and (d) less frequent injections compared toother products.

By comparison to formulations derived from other sustained release drugdelivery technologies, the risperidone sustained release delivery systemshould provide: (a) superior release kinetics with minimal burst; (b)increased duration of drug release with less frequent injections; (c)markedly improved bioavailability; (d) improved local tissue tolerancedue to a small injection volume, and (e) the ability to use of asubcutaneous injection rather than intramuscular injection. Takentogether, these features make a highly beneficial risperidone sustainedrelease delivery system.

Biodegradable Thermoplastic Polymer

The flowable composition is produced by combining a solid, biodegradablethermoplastic polymer, risperidone, a metabolite, or a prodrug thereofand a biocompatible polar aprotic organic liquid. The flowablecomposition can be administered by a syringe and needle to a patient inneed of treatment. Any suitable biodegradable thermoplastic polymer canbe employed, provided that the biodegradable thermoplastic polymer is atleast substantially insoluble in body fluid.

The biocompatible, biodegradable, thermoplastic polymer can be made froma variety of monomers which form polymer chains or monomeric unitsjoined together by linking groups. The thermoplastic polymer is composedof a polymer chain or backbone containing monomeric units joined by suchlinking groups as ester, amide, urethane, anhydride, carbonate, urea,esteramide, acetal, ketal, or orthocarbonate groups as well as any otherorganic functional group that can be hydrolyzed by enzymatic orhydrolytic reaction (i.e., is biodegradable by this hydrolytic action).The thermoplastic polymer is typically formed by reaction of startingmonomers containing the reactant groups that should form the backbonelinking groups. For example, alcohols and carboxylic acids should formester linking groups. Isocyanates and amines or alcohols shouldrespectively form urea or urethane linking groups.

Any aliphatic, aromatic, or arylalkyl starting monomer having thespecified functional groups can be used to make the thermoplasticpolymers, provided that the polymers and their degradation products arebiocompatible. The monomer or monomers used in forming the thermoplasticpolymer may be of a single or multiple identity. The resultantthermoplastic polymer should be a homopolymer formed from one monomer,or one set of monomers such as when a diol and diacid are used, or acopolymer, terpolymer, or multi-polymer formed from two or more, orthree or more, or more than three monomers or sets of monomers. Thebiocompatibility specifications of such starting monomers are known inthe art.

The thermoplastic polymers are substantially insoluble in aqueous mediaand body fluids, preferably completely insoluble in such media andfluids. They are also capable of dissolving or dispersing in selectedorganic liquids having a water solubility ranging from completelysoluble in all proportions to water insoluble. The thermoplasticpolymers also are biocompatible.

When used in the flowable composition, the thermoplastic polymer incombination with the organic liquid provides a viscosity of the flowablecomposition that varies from low viscosity, similar to that of water, toa high viscosity, similar to that of a paste, depending on the molecularweight and concentration of the thermoplastic polymer. Typically, thepolymeric composition includes about 10 wt. % to about 95 wt. %, morepreferably about 20 wt. % to about 70 wt. %, most preferably about 30wt. % to about 60 wt. %, of a thermoplastic polymer.

In one embodiment, the biodegradable, biocompatible thermoplasticpolymer can be a linear polymer, it can be a branched polymer, or it canbe a combination thereof. Any option is available according to oneembodiment. To provide a branched thermoplastic polymer, some fractionof one of the starting monomers may be at least trifunctional, andpreferably multifunctional. This multifunctional character provides atleast some branching of the resulting polymer chain. For example, whenthe polymer chosen contains ester linking groups along its polymerbackbone, the starting monomers normally should be hydroxycarboxylicacids, cyclic dimers of hydroxycarboxylic acids, cyclic trimers ofhydroxycarboxylic acids, diols, or dicarboxylic acids. Thus, to providea branched thermoplastic polymer, some fraction of a starting monomerthat is at least multifunctional, such as a triol or a tricarboxylicacid is included within the combination of monomers being polymerized toform the thermoplastic polymer. In addition, the polymers mayincorporate more than one multifunctional unit per polymer molecule, andtypically many multifunctional units depending on the stoichiometry ofthe polymerization reaction. The polymers may also optionallyincorporate at least about one multifunctional unit per polymermolecule. A so-called star or branched polymer is formed when about onemultifunctional unit is incorporated in a polymer molecule.

The preferred thermoplastic polyester may be formed from such monomersas hydroxycarboxylic acids or dimers thereof. Alternatively, athermoplastic polyester may be formed from a dicarboxylic acid and adiol. A branching monomer such as a dihydroxycarboxylic acid would beincluded with the first kind of starting monomer, or a triol and/or atricarboxylic acid would be included with the second kind of startingmonomer if a branched polyester were desired. Similarly, a triol,tetraol, pentaol, or hexaol such as sorbitol or glucose can be includedwith the first kind of starting monomer if a branched or star polyesterwere desired. The same rationale would apply to polyamides. A triamineand/or triacid would be included with starting monomers of a diamine anddicarboxylic acid. An amino dicarboxylic acid, diamino carboxylic acid,or a triamine would be included with the second kind of startingmonomer, amino acid. Any aliphatic, aromatic, or arylalkyl startingmonomer having the specified functional groups can be used to make thebranched thermoplastic polymers, provided that the polymers and theirdegradation products are biocompatible. The biocompatibilityspecifications of such starting monomers are known in the art.

The monomers used to make the biocompatible thermoplastic polymersshould produce polymers or copolymers that are thermoplastic,biocompatible, and biodegradable. Suitable thermoplastic, biocompatible,biodegradable polymers suitable for use as the biocompatiblethermoplastic branched polymers include, for example, polyesters,polylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals,polyketals, polycarbonates, polyorthocarbonates, polyorthoesters,polyphosphoesters, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), poly(amino acids), and copolymers, terpolymers,combinations, or mixtures of the above materials. Suitable examples ofsuch biocompatible, biodegradable, thermoplastic polymers are disclosed,e.g., in U.S. Pat. Nos. 4,938,763, 5,278,201, 5,324,519, 5,702,716,5,744,153, 5,990,194, 6,461,631, and 6,565,874.

The polymer composition can also include, for example, polymer blends ofthe polymers with other biocompatible polymers, so long as they do notinterfere undesirably with the biodegradable characteristics of thecomposition. Blends of the polymer with such other polymers may offereven greater flexibility in designing the precise release profiledesired for targeted drug delivery or the precise rate ofbiodegradability desired for implants.

The preferred biocompatible thermoplastic polymers or copolymers arethose which have a lower degree of crystallization and are morehydrophobic. These polymers and copolymers are more soluble in thebiocompatible organic liquids than highly crystalline polymers such aspolyglycolide, which has a high degree of hydrogen-bonding. Preferredmaterials with the desired solubility parameters are polylactides,polycaprolactones, and copolymers of these with glycolide so as toprovide more amorphous regions to enhance solubility. Generally, thebiocompatible, biodegradable thermoplastic polymer is substantiallysoluble in the organic liquid so that solutions, dispersions, ormixtures up to about 50-60 wt. % solids can be made. Preferably, thepolymers are typically completely soluble in the organic liquid so thatsolutions, dispersions, or mixtures up to about 85-98 wt. % solids canbe made. The polymers also are at least substantially insoluble in waterso that less than about 0.1 g of polymer per mL of water should dissolveor disperse in water. Preferably, the polymers are typically completelyinsoluble in water so that less than about 0.001 g of polymer per mL ofwater should dissolve or disperse in water. At this preferred level, theflowable composition with a completely water miscible organic liquidshould almost immediately transform to the solid implant.

The polymer composition can also include, for example, a biocompatible,biodegradable PLG low-burst copolymer material adapted for use in acontrolled release formulation, the low-burst copolymer material beingcharacterized by a weight average molecular weight of about 10kilodaltons to about 50 kilodaltons and a polydispersity index of about1.4 to about 2.0, and being further characterized by having separatedthere from a copolymer fraction characterized by a weight averagemolecular weight of about 4 kDa to about 10 kDa and a polydispersityindex of about 1.4 to about 2.5 (hereinafter the “removed copolymerfraction”). The PLG low-burst copolymer material is prepared from astarting PLG copolymer material without a step of hydrolysis of a highermolecular weight PLG copolymer material, by dissolving the startingcopolymer material, which is not a product of hydrolysis of a highermolecular weight PLG copolymer material, in a solvent, precipitating thelow-burst copolymer material with a non-solvent. This process, asapplied to a starting material that has never been subjected tohydrolysis, separates out an amount of the removed copolymer fractioneffective to confer desirable controlled release properties includinglow initial burst upon the copolymer. These materials, also known asPLGHp, are disclosed in copending and commonly-assigned U.S. patentapplication Ser. No. 60/901,435, filed Feb. 15, 2007, entitled“LOW-BURST POLYMERS AND METHODS TO PRODUCE POLYMERS,” which is herebyincorporated by reference.

Optionally, the delivery system may also contain a combination of anon-polymeric material and an amount of a thermoplastic polymer. Thecombination of non-polymeric material and thermoplastic polymer may beadjusted and designed to provide a more coherent risperidone sustainedrelease delivery system.

Non-polymeric materials useful are those that are biocompatible,substantially insoluble in water and body fluids, and biodegradableand/or bioerodible within the body of an animal. The non-polymericmaterial is capable of being at least partially solubilized in anorganic liquid. In the flowable composition containing some organicliquid or other additive, the non-polymeric materials are also capableof coagulating or solidifying to form a solid or gel implant upon thedissipation, dispersement or leaching of the organic liquid componentfrom the flowable composition upon contact of the flowable compositionwith a body fluid. The matrix of all embodiments of the implantincluding a non-polymeric material should have a consistency rangingfrom gelatinous to impressionable and moldable, to a hard, dense solid.

Non-polymeric materials that can be used in the delivery systemgenerally include, for example, any having the foregoingcharacteristics. Suitable useful non-polymeric materials include, forexample, sterols such as cholesterol, stigmasterol, beta-sistosterol,and estradiol; cholestery esters such as cholesteryl stearate, C₁₈-C₃₆mono-, di-, and tricylglycerides such as glyceryl monooleate, glycerylmonolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glycerylmonomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryldidocosanoate, glyceryl dimyristate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glyceryl tristearate, and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate, and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof; spingomyelins such as stearyl, palmitoyl, andtricosanyl sphingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; andcombinations and mixtures thereof. Preferred non-polymeric materialsinclude, for example, cholesterol, glyceryl monostearate, glyceryltristearate, stearic acid, stearic anhydride, glyceryl monooleate,glyceryl monolinoleate, and acetylated monoglycerides.

The polymeric and non-polymeric materials may be selected and/orcombined to control the rate of biodegradation, bioerosion, and/orbioabsorption within the implant site. Generally, the implant matrixshould breakdown over a period from about 1 week to about 12 months,preferably over a period of about 1 week to about 4 months.

Thermoplastic Polymer Molecular Weight

The molecular weight of the polymer can affect the rate of risperidone,a metabolite, or a prodrug thereof release from the implant. Under theseconditions, as the molecular weight of the polymer increases, the rateof risperidone, a metabolite, or a prodrug thereof release from thesystem decreases. This phenomenon can be advantageously used in theformulation of systems for the controlled release of risperidone, ametabolite, or a prodrug thereof. For relatively quick release ofrisperidone, a metabolite, or a prodrug thereof, low molecular weightpolymers can be chosen to provide the desired release rate. For releaseof risperidone, a metabolite, or a prodrug thereof over a relativelylong period of time, a higher polymer molecular weight can be chosen.Accordingly, a risperidone sustained release delivery system can beproduced with an optimum polymer molecular weight range for the releaseof risperidone, a metabolite, or a prodrug thereof over a selectedlength of time.

The molecular weight of a polymer can be varied by any of a variety ofmethods. The choice of method is typically determined by the type ofpolymer composition. For example, if a thermoplastic polyester is usedthat is biodegradable by hydrolysis, the molecular weight can be variedby controlled hydrolysis, such as in a steam autoclave. Typically, thedegree of polymerization can be controlled, for example, by varying thenumber and type of reactive groups and the reaction times.

The control of molecular weight and/or inherent viscosity of thethermoplastic polymer is a factor involved in the formation andperformance of the implant. In general, thermoplastic polymers withhigher molecular weight and higher inherent viscosity should provide animplant with a slower degradation rate and therefore a longer duration.Changes and fluxuations of the molecular weight of the thermoplasticpolymer following the compounding of the delivery system should resultin the formation of an implant that shows a degradation rate andduration substantially different from the degradation rate and durationdesired or predicted.

The useful thermoplastic polymers may have average molecular weightsranging from about 1 kiloDalton (kDa) to about 1,000 kDa, preferablyfrom about 2 kDa to about 500 kDa, more preferably from about 5 kDa toabout 200 kDa, and most preferably from about 5 kDa to about 100 kDa.The molecular weight may also be indicated by the inherent viscosity(abbreviated as “I.V.”, units are in deciliters/gram). Generally, theinherent viscosity of the thermoplastic polymer is a measure of itsmolecular weight and degradation time (e.g., a thermoplastic polymerwith a high inherent viscosity has a higher molecular weight and longerdegradation time). Preferably, the thermoplastic polymer has a molecularweight, as shown by the inherent viscosity, from about 0.05 dL/g toabout 2.0 dL/g (as measured in chloroform), more preferably from about0.10 dL/g to about 1.5 dL/g.

Characteristics of Preferred Polyester

The preferred thermoplastic biodegradable polymer of the flowablecomposition is a polyester. Generally, the polyester may be composed ofunits of about one or more hydroxycarboxylic acid residues wherein thedistribution of differing units may be random, block, paired, orsequential. Alternatively, the polyester may be composed of units ofabout one or more diols and about one or more dicarboxylic acids. Thedistribution should depend upon the starting materials used tosynthesize the polyester and upon the process for synthesis. An exampleof a polyester composed of differing paired units distributed in blockor sequential fashion is a poly(lactide-co-glycolide). An example of apolyester composed of differing unpaired units distributed in randomfashion is poly(lactic acid-co-glycolic acid). Suitable biodegradablethermoplastic polyesters include, for example, polylactides,polyglycolides, polycaprolactones, copolymers thereof, terpolymersthereof, and any combinations thereof. Preferably, the suitablebiodegradable thermoplastic polyester is a polylactide, a polyglycolide,a copolymer thereof, a terpolymer thereof, or a combination thereof.

The terminal groups of the poly(DL-lactide-co-glycolide) can either behydroxyl, carboxyl, or ester depending upon the method ofpolymerization. Polycondensation of lactic or glycolic acid shouldprovide a polymer with terminal hydroxyl and carboxyl groups.Ring-opening polymerization of the cyclic lactide or glycolide monomerswith water, lactic acid, or glycolic acid should provide polymers withthese same terminal groups. However, ring-opening of the cyclic monomerswith a monofunctional alcohol such as methanol, ethanol, or 1-dodecanolshould provide a polymer with about one hydroxyl group and about oneester terminal group. Ring-opening polymerization of the cyclic monomerswith a polyol such as glucose, 1,6-hexanediol, or polyethylene glycolshould provide a polymer with hydroxyl terminal groups. Such apolymerization of dimers of hydroxycarboxylic acids and a polyol is achain extension of the polymer. The polyol acts as a centralcondensation point with the polymer chain growing from the hydroxylgroups incorporated as ester moieties of the polymer. The polyol may bea diol, triol, tetraol, pentaol, or hexaol of about 2 to about 30carbons in length. Examples include saccharides, reduced saccharidessuch as sorbitol, diols such as hexane-1,6-diol, triols such as glycerolor reduced fatty acids, and similar polyols. Generally, the polyesterscopolymerized with alcohols or polyols should provide longer durationimplants.

The type, molecular weight, and amount of the preferred biodegradablethermoplastic polyester present in the flowable composition shouldtypically depend upon the desired properties of the controlled sustainedrelease implant. For example, the type, molecular weight, and amount ofbiodegradable thermoplastic polyester can influence the length of timein which the risperidone, a metabolite, or a prodrug thereof is releasedfrom the controlled sustained release implant. Specifically, in oneembodiment, the composition can be used to formulate a one monthsustained release delivery system of risperidone, a metabolite, or aprodrug thereof. In such an embodiment, the biodegradable thermoplasticpolyester can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5poly(DL-lactide-co-glycolide) having a carboxy terminal group,preferably a 50/50 poly(DL-lactide-co-glycolide) having a carboxyterminal group; can be present in about 20 wt. % to about 70 wt. % ofthe composition; and can have an average molecular weight of about10,000 Daltons to about 45,000 Daltons, or preferably about 15,000Daltons to about 40,000 Daltons.

In one embodiment, the flowable composition can be formulated to providea three month sustained release delivery system of risperidone, ametabolite, or a prodrug thereof. In such an embodiment, thebiodegradable thermoplastic polyester can be a 50/50, 55/45, 75/25,85/15, 90/10, or 95/5 poly(DL-lactide-co-glycolide) without a carboxyterminal group; preferably be a 75/25 poly(DL-lactide-co-glycolide)without a carboxy terminal group; can be present in about 20 wt. % toabout 70 wt. % of the composition; and can have an average molecularweight of about 10,000 Daltons to about 45,000 Daltons, or preferablyabout 15,000 Daltons to about 40,000 Daltons; or can be an 85/15poly(DL-lactide-co-glycolide) containing a 1,6-hexane diol chainextender, at a weight percentage of about 20 wt. % to about 70 wt. % ofthe flowable composition and at an average molecular weight of about10,000 Daltons to about 45,000 Daltons or preferably about 15,000Daltons to about 40,000 Daltons. Any polyester that has a terminalcarboxyl group can optionally be extended with a diol moiety.

In one embodiment, the flowable composition can be formulated to providea three month sustained release delivery system of risperidone, ametabolite, or a prodrug thereof. In such an embodiment, thebiodegradable thermoplastic polymer may be a non-hydrolyzed PLGlow-burst copolymer polyester material having a weight average molecularweight of about 10 kilodaltons to about 50 kilodaltons, a polydispersityindex of about 1.4 to about 2.0, and from which a copolymer fractioncharacterized by a weight average molecular weight of about 4 kDa toabout 10 kDa and a polydispersity index of about 1.4 to about 2.5 hasbeen removed.

Polar Aprotic Organic Solvent

Organic liquids suitable for use in the flowable composition arebiocompatible and display a range of solubilities in aqueous medium,body fluid, or water. That range includes complete insolubility at allconcentrations upon initial contact, to complete solubility at allconcentrations upon initial contact between the organic liquid and theaqueous medium, body fluid, or water.

While the solubility or insolubility of the organic liquid in water canbe used as a solubility guide, its water solubility or insolubility inbody fluid typically should vary from its solubility or insolubility inwater. Relative to water, body fluid contains physiologic salts, lipids,proteins, and the like, and should have a differing solvating abilityfor organic liquids. This phenomenon is similar to the classic “saltingout” characteristic displayed by saline relative to water. Body fluiddisplays similar variability relative to water but in contrast to a“salting out” factor, body fluid typically has a higher solvatingability for most organic liquids than water. This higher ability is duein part to the greater lipophilic character of body fluid relative towater, and also in part to the dynamic character of body fluid. In aliving organism, body fluid is not static but rather moves throughoutthe organism. In addition, body fluid is purged or cleansed by tissuesof the organism so that body fluid contents are removed. As a result,body fluid in living tissue should remove, solvate, or dissipate organicliquids that are utterly insoluble in water.

Pursuant to the foregoing understanding of the solubility differencesamong water, aqueous media, and body fluid, the organic liquid may becompletely insoluble to completely soluble in water when the two areinitially combined. Preferably the organic liquid is at least slightlysoluble, more preferably moderately soluble, especially more preferablyhighly soluble, and most preferably soluble at all concentrations inwater. The corresponding solubilities of the organic liquids in aqueousmedia and body fluid should tend to track the trends indicated by thewater solubilities. In body fluid, the solubilities of the organicliquids should tend to be higher than those in water.

When an organic liquid that is insoluble to slightly soluble in bodyfluid is used in any of the embodiments of the sustained releasedelivery system, it should allow water to permeate into the implanteddelivery system over a period of time ranging from seconds to weeks ormonths. This process may decrease or increase the delivery rate of therisperidone, a metabolite, or a prodrug thereof and in the case of theflowable composition, it should affect the rate of coagulation orsolidification. When an organic liquid that is moderately soluble tovery soluble in body fluid is used in any of the embodiments of thedelivery system, it should diffuse into body fluid over a period ofminutes to days. The diffusion rate may decrease or increase thedelivery rate of the risperidone, a metabolite, or a prodrug thereof.When highly soluble organic liquids are used, they should diffuse fromthe delivery system over a period of seconds to hours. Under somecircumstances, this rapid diffusion is responsible at least in part forthe so-called burst effect. The burst effect is a short-lived but rapidrelease of risperidone, a metabolite, or a prodrug thereof uponimplantation of the delivery system followed by a long-lived, slowrelease of risperidone, a metabolite, or a prodrug thereof.

Organic liquids used in the delivery system include, for example,aliphatic, aryl, and arylalkyl; linear, cyclic, and branched organiccompounds that are liquid or at least flowable at ambient andphysiological temperature and contain such functional groups asalcohols, alkoxylated alcohols, ketones, ethers, polymeric ethers,amides, esters, carbonates, sulfoxides, sulfones, any other functionalgroup that is compatible with living tissue, and any combinationthereof. The organic liquid preferably is a polar aprotic, or polarprotic organic solvent. Preferably, the organic liquid has a molecularweight in the range of about 30 to about 1000.

Preferred biocompatible organic liquids that are at least slightlysoluble in aqueous or body fluid include, for example,N-methyl-2-pyrrolidone, 2-pyrrolidone; (C₁-C₁₅) alcohols, diols, triols,and tetraols such as ethanol, glycerin, propylene glycol, and butanol;(C₃-C₁₅) alkyl ketones such as acetone, diethyl ketone, and methyl ethylketone; (C₃-C₁₅) esters and alkyl esters of mono-, di-, andtricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate,methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethylglutonate, tributyl citrate, diethyl succinate, tributyrin, isopropylmyristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, andglyceryl triacetate; (C₁-C₁₅) amides such as dimethylformamide,dimethylacetamide, and caprolactam; (C₃-C₂₀) ethers such astetrahydrofuran or solketal; tweens, triacetin, decylmethylsulfoxide,dimethyl sulfoxide, oleic acid, 1-dodecylazacycloheptan-2-one,N-methyl-2-pyrrolidone, esters of carbonic acid and alkyl alcohols suchas propylene carbonate, ethylene carbonate, and dimethyl carbonate;alkyl ketones such as acetone and methyl ethyl ketone; alcohols such assolketal, glycerol formal, and glycofurol; dialkylamides such asdimethylformamide, dimethylacetamide, dimethylsulfoxide, anddimethylsulfone; lactones such as epsilon-caprolactone andbutyrolactone; cyclic alkyl amides such as caprolactam; triacetin anddiacetin; aromatic amides such as N,N-dimethyl-m-toluamide; and mixturesand combinations thereof. Preferred solvents include, for example,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate, solketal, triacetin, glycerol formal,isopropylidene glycol, and glycofurol.

Other preferred organic liquids are benzyl alcohol, benzyl benzoate,dipropylene glycol, tributyrin, ethyl oleate, glycerin, glycofural,isopropyl myristate, isopropyl palmitate, oleic acid, polyethyleneglycol, propylene carbonate, and triethyl citrate. The most preferredsolvents are N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide,triacetin, and propylene carbonate because of their solvating abilityand their compatibility.

The type and amount of biocompatible organic liquid present in theflowable composition should typically depend on the desired propertiesof the controlled release implant as described in detail below.Preferably, the flowable composition includes about 10 wt. % to about 90wt. % or more preferably about 30 wt. % to about 70 wt. % of an organicliquid.

The solubility of the biodegradable thermoplastic polymers in thevarious organic liquids should differ depending upon theircrystallinity, their hydrophilicity, hydrogen-bonding, and molecularweight. Lower molecular-weight polymers should normally dissolve morereadily in the organic liquids than high-molecular-weight polymers. As aresult, the concentration of a thermoplastic polymer dissolved in thevarious organic liquids should differ depending upon type of polymer andits molecular weight. Moreover, the higher molecular-weightthermoplastic polymers should tend to give higher solution viscositiesthan the low-molecular-weight materials.

When the organic liquid forms part of the flowable composition, itfunctions to enable easy, non-surgical placement of the sustainedrelease delivery system into living tissue. It also facilitatestransformation of the flowable composition to an in situ formed implant.Although it is not meant as a limitation of the invention, it isbelieved that the transformation of the flowable composition is theresult of the dissipation of the organic liquid from the flowablecomposition into the surrounding body fluid and tissue and the infusionof body fluid from the surrounding tissue into the flowable composition.It is believed that during this transformation, the thermoplasticpolymer and organic liquid within the flowable composition partitioninto regions rich and poor in polymer.

For the flowable composition, the concentration of the thermoplasticpolymer in the organic liquid should range from about 0.01 g per mL oforganic liquid to a saturated concentration. Typically, the saturatedconcentration should be in the range of about 80 to about 95 wt. %solids or about 4 gm per mL to about 5 gm per mL of organic liquid,assuming that the organic liquid weighs approximately 1 gm per mL.

For polymers that tend to coagulate slowly, a solvent mixture can beused to increase the coagulation rate. In essence, one liquid componentof the solvent mixture is a good solvent for the polymer, and the otherliquid component of the solvent mixture is a poorer solvent or anon-solvent. The two liquids are mixed at a ratio such that the polymeris still soluble but precipitates with the slightest increase in theamount of non-solvent, such as water in a physiological environment. Bynecessity, the solvent system should be miscible with both the polymerand water. An example of such a binary solvent system is the use ofN-methyl-2-pyrrolidone and ethanol. The addition of ethanol to theN-methyl-2-pyrrolidone/polymer solution increases its coagulation rate.

For the formed implant, the presence of the organic liquid can serve toprovide the following properties: plasticization, moldability,flexibility, increased or decreased homogeneity, increased or decreasedrelease rate for the bioactive agent, leaching, promotion or retardationof body fluid influx into the implant, patient comfort, compatibility ofthermoplastic polymer and bioactive agent, and the like. Generally theconcentration of organic liquid in the formed implant may range fromabout 0.001 wt. % to as much as about 30 wt. %. Generally, theconcentration should be less than an amount that would cause reversionof the formed implant into a flowable composition. Also, the organicliquid may preferentially be chosen so as to display less thansubstantial ability to dissolve the thermoplastic polymer.

The pliability of the implant can be substantially maintained throughoutits life if additives such as the organic liquid are maintained in theimplant. Such additives also can act as a plasticizer for thethermoplastic polymer and at least in part may remain in the implant.One such additive having these properties is an organic liquid of lowwater solubility to water insolubility. Such an organic liquid providingthese pliability and plasticizing properties may be included in thedelivery system as the sole organic liquid or may be included inaddition to an organic liquid that is moderately to highly watersoluble.

Organic liquids of low water solubility or water insolubility, such asthose forming aqueous solutions of no more than about 5% by weight inwater, can function as a pliability, plasticizing component, and inaddition can act as the solvating component for the flowable compositionembodiment. Such organic liquids can act as plasticizers for thethermoplastic polymer. When the organic liquid has these properties, itis a member of a subgroup of organic liquids termed “plasticizer.” Theplasticizer influences the pliablity and moldability of the implantcomposition such that it is rendered more comfortable to the patientwhen implanted. Moreover, the plasticizer has an effect upon the rate ofsustained release of risperidone, a metabolite, or a prodrug thereofsuch that the rate can be increased or decreased according to thecharacter of the plasticizer incorporated into the implant composition.In general, the organic liquid acting as a plasticizer is believed tofacilitate molecular movement within the solid or gel thermoplasticmatrix. The plasticizing capability enables polymer molecules of thematrix to move relative to each other so that pliability and easymoldability are provided. The plasticizing capability also enables easymovement of risperidone, a metabolite, or a prodrug thereof so that insome situations, the rate of sustained release is either positively ornegatively affected.

High Water Solubility Organic Liquids

A moderate to highly water soluble organic liquid can be generally usedin the flowable composition, especially when pliability should not be anissue after formation of the implant. Use of the highly water solubleorganic liquid should provide an implant having the physicalcharacteristics of an implant made through direct insertion of theflowable composition.

Use of a moderate to highly water soluble organic liquid in flowablecomposition should facilitate intimate combination and mixture of theother components therein. It should promote solid or gel homogeneity andpliability of an ex vivo formed implant so that such an implant can bereadily inserted into appropriate incisions or trocar placements intissue.

Useful, highly water soluble organic liquids include, for example,substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP)and 2-pyrrolidone; (C₂-C₁₀)alkanoic acids such as acetic acid and lacticacid, esters of hydroxy acids such as methyl lactate, ethyl lactate,alkyl citrates, and the like; monoesters of polycarboxylic acids such asmonomethyl succinate acid, monomethyl citric acid, and the like; etheralcohols such as glycofurol, glycerol formal, isopropylidene glycol, and2,2-dimethyl-1,3-dioxolone-4-methanol; Solketal; dialkylamides such asdimethylformamide and dimethylacetamide; dimethylsulfoxide (DMSO) anddimethylsulfone; lactones such as epsilon, caprolactone, andbutyrolactone; cyclic alkyl amides such as caprolactam; and mixtures andcombinations thereof. Preferred organic liquids include, for example,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,glycofurol, glycerol formal, and isopropylidene glycol.

Low Water Solubility Organic Liquids/Solvents

As described above, an organic liquid of low or no water solubility(hereinafter low/no liquid) may also be used in the sustained releasedelivery system. Preferably, a low/no liquid is used when it isdesirable to have an implant that remains pliable, is to be extrudableis to have an extended release and the like. For example, the releaserate of the biologically active agent can be affected under somecircumstances through the use of a low/no liquid. Typically suchcircumstances involve retention of the organic liquid within the implantproduct and its function as a plasticizer or rate modifier.

Suitable low or nonsoluble organic liquids include, for example, estersof carbonic acid and aryl alcohols such as benzyl benzoate;(C₄-C₁₀)alkyl alcohols; (C₁-C₆)alkyl(C₂-C₆) alkanoates; esters ofcarbonic acid and alkyl alcohols such as propylene carbonate, ethylenecarbonate, and dimethyl carbonate, alkyl esters of mono-, di-, andtricarboxylic acids, such as 2-ethyoxyethyl acetate, ethyl acetate,methyl acetate, ethyl butyrate, diethyl malonate, diethyl glutonate,tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate,dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethylcitrate, triethyl citrate, acetyl tributyl citrate, and glyceryltriacetate; alkyl ketones such as methyl ethyl ketone; as well as othercarbonyl, ether, carboxylic ester, amide, and hydroxy containing liquidorganic compounds having some solubility in water. Propylene carbonate,ethyl acetate, triethyl citrate, isopropyl myristate, and glyceryltriacetate are preferred because of biocompatibility and pharmaceuticalacceptance.

Additionally, mixtures of the foregoing high, low, or no solubilityorganic liquids providing varying degrees of solubility for the matrixforming material can be used to alter the life time, rate of bioactiveagent release, and other characteristics of the implant. Examplesinclude a combination of N-methyl-2-pyrrolidone and propylene carbonate,which provides a more hydrophobic solvent than N-methyl-2-pyrrolidonealone, and a combination of N-methyl-2-pyrrolidone and polyethyleneglycol, which provides a more hydrophilic solvent thanN-methyl-2-pyrrolidone alone.

The organic liquid for inclusion in the composition should bebiocompatible. Biocompatible means that as the organic liquid dispersesor diffuses from the composition, it does not result in substantialtissue irritation or necrosis surrounding the implant site.

Organic Liquid for the Preferred Flowable Composition

For the preferred flowable composition incorporating a thermoplasticpolyester, any suitable polar aprotic organic liquid can be employed,provided that the suitable polar aprotic solvent displays a body fluidsolubility within a range of completely soluble in all proportions tovery slightly soluble. Suitable polar aprotic organic liquids aredisclosed, e.g., in ALDRICH HANDBOOK OF FINE CHEMICALS AND LABORATORYEQUIPMENT, Milwaukee, Wis. (2000) and in U.S. Pat. Nos. 5,324,519,4,938,763, 5,702,716, 5,744,153, and 5,990,194. A suitable polar aproticliquid should be able to diffuse over time into body fluid so that theflowable composition coagulates or solidifies. The diffusion may berapid or slow. It is also preferred that the polar aprotic liquid forthe biodegradable polymer be non-toxic and otherwise biocompatible.

The polar aprotic organic liquid is preferably biocompatible. Suitablepolar aprotic organic liquid include, for example, those having an amidegroup, an ester group, a carbonate group, a ketone, an ether, a sulfonylgroup, or a combination thereof.

Preferably, the polar aprotic organic liquid comprisesN-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, or anycombination thereof. More preferably, the polar aprotic organic solventis N-methyl-2-pyrrolidone.

The solubility of the biodegradable thermoplastic polyesters in thevarious polar aprotic liquids should differ depending upon theircrystallinity, their hydrophilicity, hydrogen-bonding, and molecularweight. Thus, not all of the biodegradable thermoplastic polyestersshould be soluble to the same extent in the same polar aprotic organicliquid, but each biodegradable thermoplastic polymer or copolymer shouldbe soluble in its appropriate polar aprotic solvent. Lowermolecular-weight polymers should normally dissolve more readily in theliquids than high-molecular-weight polymers. As a result, theconcentration of a polymer dissolved in the various liquids shoulddiffer depending upon type of polymer and its molecular weight.Conversely, the higher molecular-weight polymers should normally tend tocoagulate or solidify faster than the very low-molecular-weightpolymers. Moreover the higher molecular-weight polymers should tend togive higher solution viscosities than the low-molecular-weightmaterials.

For example, low-molecular-weight polylactic acid formed by thecondensation of lactic acid should dissolve in N-methyl-2-pyrrolidone(NMP) to give about 73% by weight solution which still flows easilythrough a 23-gauge syringe needle, whereas a higher molecular-weightpoly(DL-lactide) (DL-PLA) formed by the additional polymerization ofDL-lactide gives the same solution viscosity when dissolved inN-methyl-2-pyrrolidone at about 50% by weight. The highermolecular-weight polymer solution coagulates immediately when placedinto water. The low-molecular-weight polymer solution, although moreconcentrated, tends to coagulate very slowly when placed into water.

It has also been found that solutions containing very highconcentrations of high molecular weight polymers sometimes coagulate orsolidify slower than more dilute solutions. It is believed that the highconcentration of polymer impedes the diffusion of solvent from withinthe polymer matrix and consequently prevents the permeation of waterinto the matrix where it can precipitate the polymer chains. Thus, thereis an optimum concentration at which the solvent can diffuse out of thepolymer solution and water penetrates within to coagulate the polymer.

The concentration and species of the polar aprotic organic liquid forthe preferred flowable composition incorporating a thermoplasticpolyester should typically depend upon the desired properties of thecontrolled release implant. For example, the species and amount ofbiocompatible polar aprotic solvent can influence the length of time inwhich the risperidone, a metabolite, or a prodrug thereof is releasedfrom the controlled release implant.

Specifically, in one embodiment, the flowable composition can be used toformulate a one month delivery system of risperidone, a metabolite, or aprodrug thereof. In such an embodiment, the biocompatible polar aproticsolvent can preferably be N-methyl-2-pyrrolidone and can preferablypresent in about 30 wt. % to about 70 wt. % of the composition.

Alternatively, in another embodiment, the composition can be used toformulate a three month delivery system of risperidone, a metabolite, ora prodrug thereof. In such an embodiment, the biocompatible polaraprotic solvent can preferably be N-methyl-2-pyrrolidone and canpreferably present in about 30 wt. % to about 70 wt. % of thecomposition.

Risperidone

Risperidone (also known as4-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-1-piperidyl]ethyl]-3-methyl-2,6-diazabicyclo[4.4.0]deca-1,3-dien-5-oneand marketed under the trade name RISPERDAL®) is a psychotropic agentbelonging to the chemical class of benzisoxazole derivatives.Risperidone, a metabolite, or a prodrug thereof may be administered inits unneutralized basic form, or as a salt of an organic or inorganicacid. Examples include the risperidone, a metabolite, or a prodrugthereof salts wherein the gegenion (counter-ion) is acetate, propionate,tartrate, malonate, chloride, sulfate, bromide, and otherpharmaceutically acceptable organic and inorganic acid gegenions.

Risperidone, a metabolite, or a prodrug thereof may be lyophilized priorto use. Typically, the risperidone, a metabolite, or a prodrug thereofmay be dissolved in an aqueous solution, sterile filtered, andlyophilized in a syringe. In a separate process, the thermoplasticpolymer/organic liquid solution can be filled into second syringe. Thetwo syringes can be coupled together and the contents can be drawn backand forth between the two syringes until the thermoplastic polymer,organic liquid, and the risperidone, a metabolite, or a prodrug thereofare effectively mixed together, forming a flowable composition. Theflowable composition can be drawn into one syringe. The two syringes canbe disconnected and a needle attached to the syringe containing theflowable composition. The flowable composition can be injected throughthe needle into the body. The flowable composition can be formulated andadministered to a patient as described in, e.g., U.S. Pat. Nos.5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194; or asdescribed herein. Once administered, the organic liquid dissipates, theremaining polymer gels or solidifies, and a matrix structure is formed.The organic liquid should dissipate and the polymer should solidify orgel so as to entrap or encase the risperidone, a metabolite, or aprodrug thereof within the matrix.

The release of risperidone, a metabolite, or a prodrug thereof from theimplant should follow the same general rules for release of a drug froma monolithic polymeric device. The release of risperidone, a metabolite,or a prodrug thereof can be affected by the size and shape of theimplant, the loading of risperidone, a metabolite, or a prodrug thereofwithin the implant, the permeability factors involving the risperidone,a metabolite, or a prodrug thereof and the particular polymer, and thedegradation of the polymer. Depending upon the amount of risperidone, ametabolite, or a prodrug thereof selected for delivery, the aboveparameters can be adjusted by one skilled in the art of drug delivery togive the desired rate and duration of release.

The amount of risperidone, a metabolite, or a prodrug thereofincorporated into the sustained release delivery system depends upon thedesired release profile, the concentration of risperidone, a metabolite,or a prodrug thereof used for a biological effect, and the length oftime that the risperidone, a metabolite, or a prodrug thereof has to bereleased for treatment. There is no upper limit on the amount ofrisperidone, a metabolite, or a prodrug thereof incorporated into thesustained release delivery system except for that of an acceptablesolution or dispersion viscosity for injection through a syringe needle.The lower limit of risperidone, a metabolite, or a prodrug thereofincorporated into the sustained release delivery system is dependentupon the activity of the risperidone, a metabolite, or a prodrug thereofand the length of time needed for treatment. Specifically, in oneembodiment, the sustained release delivery system can be formulated toprovide a one month release of risperidone, a metabolite, or a prodrugthereof. In such an embodiment, the risperidone, a metabolite, or aprodrug thereof can preferably be present in about 0.5 wt. % to about 50wt. %, preferably about 1 wt. % to about 30 wt. % of the composition.Alternatively, in another embodiment, the sustained release deliverysystem can be formulated to provide a three month delivery ofrisperidone, a metabolite, or a prodrug thereof. In such an embodiment,the risperidone, a metabolite, or a prodrug thereof can preferably bepresent in about 0.5 wt. % to about 50 wt. %, preferably about 1 wt. %to about 30 wt. % of the composition. The gel or solid implant formedfrom the flowable composition should release the risperidone, ametabolite, or a prodrug thereof contained within its matrix at acontrolled rate until the implant is effectively depleted ofrisperidone, a metabolite, or a prodrug thereof.

Risperidone is extensively metabolized in the liver. The main metabolicpathway is through hydroxylation of risperidone to 9-hydroxyrisperidoneby the enzyme, CYP 2D6. A minor metabolic pathway is throughN-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similarpharmacological activity as risperidone. Consequently, the clinicaleffect of the drug (e.g., the active moiety) results from the combinedconcentrations of risperidone plus 9-hydroxyrisperidone.

Adjuvants and Carriers

The sustained release delivery system may include, for example, arelease rate modifier to alter the sustained release rate ofrisperidone, a metabolite, or a prodrug thereof from the implant matrix.The use of a release rate modifier may either decrease or increase therelease of risperidone, a metabolite, or a prodrug thereof in the rangeof multiple orders of magnitude (e.g., 1 to 10 to 100), preferably up toa ten-fold change, as compared to the release of risperidone, ametabolite, or a prodrug thereof from an implant matrix without therelease rate modifier.

With the addition of a hydrophobic release rate modifier such ashydrophobic ethyl heptanoate, to the sustained release delivery system,and formation of the implant matrix through interaction of the flowablecomposition and body fluid, the release rate of risperidone, ametabolite, or a prodrug thereof can be slowed. Hydrophilic release ratemodifiers such as polyethylene glycol may increase the release of therisperidone, a metabolite, or a prodrug thereof. By an appropriatechoice of the polymer molecular weight in combination with an effectiveamount of the release rate modifier, the release rate and extent ofrelease of a risperidone, a metabolite, or a prodrug thereof from theimplant matrix may be varied, for example, from relatively fast torelatively slow.

Useful release rate modifiers include, for example, organic substanceswhich are water-soluble, water-miscible, or water insoluble (i.e.,hydrophilic to hydrophobic).

The release rate modifier is preferably an organic compound which isthought to increase the flexibility and ability of the polymer moleculesand other molecules to slide past each other even though the moleculesare in the solid or highly viscous state. Such an organic compoundpreferably includes a hydrophobic and a hydrophilic region. It ispreferred that a release rate modifier is compatible with thecombination of polymer and organic liquid used to formulate thesustained release delivery system. It is further preferred that therelease rate modifier is a pharmaceutically-acceptable substance.

Useful release rate modifiers include, for example, fatty acids,triglycerides, other like hydrophobic compounds, organic liquids,plasticizing compounds, and hydrophilic compounds. Suitable release ratemodifiers include, for example, esters of mono-, di-, and tricarboxylicacids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate,diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyladipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate,glycerol triacetate, di(n-butyl) sebecate, and the like; polyhydroxyalcohols, such as propylene glycol, polyethylene glycol, glycerin,sorbitol, and the like; fatty acids; triesters of glycerol, such astriglycerides, epoxidized soybean oil, and other epoxidized vegetableoils; sterols, such as cholesterol; alcohols, such as (C₆-C₁₂) alkanols,2-ethoxyethanol, and the like. The release rate modifier may be usedsingly or in combination with other such agents.

Suitable combinations of release rate modifiers include, for example,glycerin/propylene glycol, sorbitol/glycerin, ethylene oxide/propyleneoxide, butylene glycol/adipic acid, and the like. Preferred release ratemodifiers include, for example, dimethyl citrate, triethyl citrate,ethyl heptanoate, glycerin, and hexanediol.

The amount of the release rate modifier included in the flowablecomposition should vary according to the desired rate of release of therisperidone, a metabolite, or a prodrug thereof from the implant matrix.Preferably, the sustained release delivery system contains about 0.5 toabout 30%, preferably about 5 to about 10%, of a release rate modifier.

Other solid adjuvants may also be optionally combined with the sustainedrelease delivery system to act as carriers, especially isolationcarriers. These include, for example, additives or excipients such as astarch, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, and/orpolyvinylpyrrolidone.

Additional adjuvants may include, for example, oils such as peanut oil,sesame oil, cottonseed oil, corn oil, and olive oil as well as esters offatty acids such as ethyl oleate, isopropyl myristate, fatty acidglycerides, and acetylated fatty acid glycerides. Also included arealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol); petroleum hydrocarbons such asmineral oil and petrolatum may also be used in the formulations.Pectins, carbomers, methyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, or carboxymethyl cellulose may also beincluded. These compounds can serve as isolation carriers by coating therisperidone, a metabolite, or a prodrug thereof thereby preventing itscontact with the organic solvent and other ingredients of the flowablecomposition. As isolation carriers, these compounds also help lower theburst effect associated with the coagulation of the flowable compositionin situ.

Optionally, other compounds such as, but not limited to, stabilizers,antimicrobial agents, antioxidants, pH modifiers, bioavailabilitymodifiers, and combinations of these are included. Emulsifiers andsurfactants such as fatty acids or a non-ionic surfactants includingnatural or synthetic polar oil, fatty acid esters, polyol ethers, andmono-, di-, or tri-glycerides may also be included.

The Implant

When the implant is formed, the implant has the physical state of asolid or a gel. The solid embodiments may be rigid so that they cannotbe flexed or bent by squeezing them between the fingers or they may beflexible or bendable so that they can be compressed or flexed out oforiginal shape by squeezing between the fingers (i.e., a low amount offorce). The gel embodiments may be jelly-like in consistency and shouldflow under pressure. The thermoplastic polymer functions as a matrix inthese embodiments to provide integrity to the single body solid or geland to enable controlled release of the bioactive agent uponimplantation.

The thermoplastic polymer matrix is preferably a solid matrix andespecially preferably is microporous. In an embodiment of themicroporous solid matrix, there is a core surrounded by a skin. The corepreferably contains pores of diameters from about 1 to about 1000microns. The skin preferably contains pores of smaller diameters thanthose of the core pores. In addition, the skin pores are preferably of asize such that the skin is functionally non-porous in comparison withthe core.

Because all of the components of the implant are biodegradable or can beswept away from the implant site by body fluid and eliminated from thebody, the implant eventually disappears. Typically the implantcomponents complete their biodegradation or disappearance after therisperidone, a metabolite, or a prodrug thereof has been typicallycompletely released. The structure of the thermoplastic polymer, itsmolecular weight, the density and porosity of the implant, and the bodylocation of the implant all affect the biodegradation and disappearancerates.

The implant is typically formed subcutaneously in a patient. It can bemolded in place upon injection to provide comfort to the patient. Theimplant volume typically may be between about 0.25 mL to about 3 mL insize.

Therapeutic Use

Surprisingly, it has been discovered that the sustained release deliverysystem is more effective in delivering risperidone than the RISPERDAL®CONSTA® product. Specifically, as shown in the Examples below, the bloodlevels of risperidone obtained with the sustained release deliverysystem are from about 0 nanograms per milliliter (ng/mL) to about 500ng/mL.

In general, any disease which may be ameliorated, treated, cured, orprevented by administration of risperidone, a metabolite, or a prodrugthereof or a risperidone analog may be treated by administration of theflowable composition. These diseases relate to mental impairments. Thefollowing specific malconditions are exemplary of such diseases. Thesemay all be treated by appropriate, effective administration of aflowable composition formulated to deliver an effective amount ofrisperidone, a metabolite, or a prodrug thereof. These malconditionsinclude: schizophrenia, bipolar disorder, psychotic depression,obsessive-compulsion disorder, Tourette syndrome, autism spectrumdisorders, and the like.

Dosages

The amount of flowable composition administered should typically dependupon the desired properties of the controlled release implant. Forexample, the amount of flowable composition can influence the length oftime in which the risperidone, a metabolite, or a prodrug thereof isreleased from the controlled release implant. Specifically, in oneembodiment, the composition can be used to formulate a one monthdelivery system of risperidone, a metabolite, or a prodrug thereof. Insuch an embodiment, about 0.20 mL to about 2.0 mL of the flowablecomposition can be administered. Alternatively, in another embodiment,the composition can be used to formulate a three month delivery systemof risperidone, a metabolite, or a prodrug thereof. In such anembodiment, about 0.75 mL to about 1.0 mL of the flowable compositioncan be administered.

The amount of risperidone, a metabolite, or a prodrug thereof within theflowable composition and the resulting implant should depend upon thedisease to be treated, the length of duration desired, and thebioavailability profile of the implant. Generally, the effective amountshould be within the discretion and wisdom of the patient's attendingphysician. Guidelines for administration include, for example, doseranges of from about 1 to about 16 milligrams (mg) of risperidone, ametabolite, or a prodrug thereof per day, preferably from about 1 toabout 5 milligrams (mg) of risperidone, a metabolite, or a prodrugthereof per day, as applied for schizophrenia, bipolar disorder,psychotic depression, obsessive-compulsion disorder, Tourette syndrome,and autism spectrum disorders. The typical flowable compositioneffective for such sustained delivery over a 1 month period shouldcontain from about 3 to about 300 mg of risperidone, a metabolite, or aprodrug thereof per ml of total volume of flowable composition. Theinjection volume should range from about 0.2 to about 2.0 mL perimplant. The typical flowable composition effective for such sustaineddelivery of a 3 month period should contain from about 9 to about 900 mgof risperidone, a metabolite, or a prodrug thereof per ml of totalvolume of flowable composition. The injection volume should range from0.75 to about 1.0 mL per implant. The polymer formulation should be theprimary factor for obtaining the longer sustained release, as discussedabove.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention should now be illustrated with the following non-limitingexamples.

The following Examples employ the ATRIGEL® formulation ofpoly(lactide-co-glycolide) and N-methyl-2-pyrrolidone in combinationwith risperidone as the flowable composition.

EXAMPLES

In the following Examples, ATRIGEL®/Risperidone refers toATRIGEL®/Risperidone formulations; ATRIGEL® is a registered Trademark ofQLT-USA, Fort Collins, Colo. The particular form of ATRIGEL® productused in these examples is provided with the examples. Unless otherwiseindicated, the ATRIGEL® product is the thermoplastic polymerpoly(lactide-co-glycolide) (PLG), the thermoplastic polymerpoly(lactide-co-glycolide extended with 1,6-hexane diol) (PLGH), orPLGHp in the organic solvent N-methyl-2-pyrrolidone. RISPERDAL® andRISPERDAL® CONSTA® are registered Trademarks of Janssen, L.P.,Titusville, N.J.

The ATRIGEL® drug delivery system is a biodegradable polymeric deliverysystem that can be injected as a liquid. Upon injection of theformulation, the polymer solidifies encapsulating the drug. As theprocess of biodegradation begins, the drug is slowly released. Therelease rate of drugs from this type of delivery system can becontrolled by the type and molecular weight of the polymer and drug loadof the constituted product. Therefore, the system can be tailored tomeet the needs of the patient.

The ATRIGEL® Delivery System is currently used in the Food and DrugAdministration approved products ELIGARD™ (one, three, and four-monthsubcutaneous depot formulations of leuprolide acetate) and ATRIDOX®(doxycycline hyclate applied to the periodontal pocket). Clinicalstudies and post-marketing experience with these products demonstratethat the ATRIGEL® Delivery System itself is well tolerated and providesconsistent, sustained release of the incorporated drug over thedesignated dosing period.

In addition as demonstrated by the clinical results provided below, theflowable compositions have no lag phase, and continuous therapeuticplasma levels. The 1- and 3-month flowable compositions provide analternative drug delivery technology that addresses these as well asseveral other drawbacks of currently marketed RISPERDAL® and RISPERDAL®CONSTA® products.

The advantages of the approach using the flowable composition to solvethese problems include: a) a rapid therapeutic response with no lagtime; b) a subcutaneous injection that is patient friendly; c) lesspain; d) no muscle damage and scarring; e) smaller-gauge needles; f)less volume; g) ease-of-administration; h) quick and easy preparation;i) no clogging of the needle; and j) removable up to eight weeks, unlikepreparations using microspheres.

As a result, the flowable compositions provide superior pharmacokineticsand higher bioavailability relative to other known delivery systemsproviding risperidone. These features represent improvements regardlessof the particular application, i.e. any risperidone responsive disease.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

SOURCES OF MATERIALS Abbreviation Chemical Name and Supplier ACNAcetonitrile Sigma-Aldrich, St. Louis, MO. 50/50 PLG (InV BirminghamPolymer, Inc. 0.10 dL/g) Birmingham, AL. Lot #5 05-01-1A 50/50 PLGH (InVAlkermes, Inc. 0.36 dL/g) Cambridge, MA. Lot # 1010-492 50/50 PLGH (InVBoehringer Ingelheim 0.18 dL/g) Ridgefield, CT. Lot # 1005072 75/25 PLG(InV Birmingham Polymer, Inc. 0.19 dL/g) Birmingham, AL. Lot # D9908250/50 PLG (InV Boehringer Ingelheim 0.33 dL/g) Ridgefield, CT. Lot #1004925 50/50 PLG (InV Birmingham Polymer, Inc. 0.24 dL/g) Birmingham,AL. Lot # 112-99-1 50/50 PLG (InV Boehringer Ingelheim 0.19 dL/g)Ridgefield, CT. Lot # 1004925 50/50 PLGH (InV Boehringer Ingelheim 0.49dL/g) Ridgefield, CT. Lot # 290541 65/35 PLGH (InV Alkermes, Inc. 0.20dL/g) Cambridge, MA. Lot # 1291-536 65/35 PLGH (MW QLT USA Inc. 37 kDa)Fort Collins, CO. Lot # ALN 1654-34 75/25 PLGH (InV Alkermes, Inc. 0.15dL/g) Cambridge, MA. Lot # 1151-514 75/25 PLGH (InV Alkermes, Inc. 0.24dL/g) Cambridge, MA. Lot # 00-141-150 75/25 PLGH (InV BirminghamPolymer, Inc. 0.26 dL/g) Birmingham, AL. Lot # D99140 80/20 PLGH (MW QLTUSA Inc. 42 kDa) Fort Collins, CO. Lot # 2012-61 85/15 PLGH (InVAdvanced Polymer Technology 0.27 dL/g) Lot # A140-13 50/50 PLG/PEG5000Birmingham Polymer, Inc. (InV 0.79 dL/g) Birmingham, AL. Lot # D9901170/30 PLG/PEG5000 Birmingham Polymer, Inc. (InV 0.79 dL/g) Birmingham,AL. Lot # D97132 PEG8000-PLG QLT USA Inc. (InV 0.29 dL/g) Fort Collins,CO. Lot # ALN 1654-76 3-Hydroxy-2- Acros Organics Naphthoic Acid Geel,Belgium Lot # 03311 Citric Acid Fisher Scientific Anhydrous Chicago, ILLot # 006630 Cholesterol Sigma-Aldrich, St. Louis, MO. Lot # 02653 EDTAEthylenediaminetetraacetic acid Sigma-Aldrich, St. Louis, MO. EL EthylLactate Sigma-Aldrich, St. Louis, MO. Glacial Acidic Fisher ScientificAcid Chicago, IL Lot # 002418 Hydrochloric Acid J T Baker Chicago, ILLot # V28511 Mannitol Roquette Lestrem, France RDC # 709609 NMPN-Methyl-2-Pyrrolidone International Specialty Products Wayne, NJ.Pamoic Acid Sigma-Aldrich, St. Louis, MO. Lot # 03287 PEIPolyethyleneimine Sigma-Aldrich, St. Louis, MO. Tartaric Acid SpectrumAnhydrous Lot # PL0341 Risperidone Medichem Lot # A010580 RISPERDAL ®Janssen, L. P., CONSTA ® Titusville, NJ. Lot # 5NA467 RISPERDAL ®Janssen, L. P. tablets Titusville, NJ.

LIST OF ABBREVIATIONS AND DEFINITION OF TERMS Abbreviation Definition50/50 Weight ratio of lactide to glycolide in the polymer 65/35 75/2585/15 95/5 ATRIGEL ® General name given to a solution prepared bydissolving poly(lactide-co-glycolide) polymers in a biocompatiblesolvent (typically NMP) AUC Area under the plasma concentration-timeprofile AUC₀₋₂₄ Area under the plasma concentration-time profile fromtime 0 to 24 hours post-dose AUC_(0-inf) Area under the plasmaconcentration-time profile from time 0 to infinity cP centiPoise C_(max)Maximum plasma concentration CV(%) Coefficient of variation, expressedas a percentage FDA Food and Drug Administration HPLC High PerformanceLiquid Chromatography i.m. Intramuscular i.v. Intravenous InV InherentViscosity (dL/g) Ke Apparent terminal phase rate constant kDa kilodaltonKGy kiloGray Max Maximum Mg Milligram Min Minimum Min Minute mLMilliliter MW Molecular Weight PBS Phosphate Buffered Saline PDPharmacodynamic PEG Polyethylene glycol PLA Polylactide PLGPoly(lactide-co-glycolide) with methyl end group PLCPoly(lactide-co-caprolactone) PLGH Poly(DL-lactide-co-glycolide) with acarboxylic acid end group PLGHp Poly(DL-lactide-co-glycolide) with afree carboxylic acid group on at least one end of each polymer chain)that has been purified by a solvent/nonsolvent precipitation method. PKPharmacokinetic PPM Parts per million RSP Risperidone RT RoomTemperature s.c. Subcutaneous SD Standard deviation SE Standard error TATest Article T_(m) Time to maximum plasma concentration level

Test Procedures Text Article Preparation Procedure Using PLGH

Preparation of Polymer Solutions

Polymer stock solutions were prepared by weighing a known amount of eachpolymer solid into individual 20 mL scintillation vials. A known amountof N-methyl-2-pyrrolidone was added to each polymer and the vials wereplaced on a horizontal jar mill. The vials were rotated overnight toproduce a visually clear polymer solution indicating dissolution of thepolymer. Sterilization of the polymer solution was accomplished by gammairradiation.

Preparation of Test Article Syringes

The “B” syringes (male syringes) contained risperidone powder and wereprepared by weighing drug powder into 1.25 mL Becton Dickinson (BD) malesyringes. The “A” syringes (female syringes) were prepared by weighingATRIGEL® polymer stock solutions into 1.0 mL female syringes.

Preparation of Test Articles (Reconstituted Formulation) for Injection

Immediately prior to injection, “A” and “B” syringes were coupled andmixed by cycling the contents from one syringe to the other for 90cycles. The mixed formulation was finally transferred to the male dosingsyringe for injection. Some of the formulations were roll mixed.Risperidone and selected ATRIGEL® were weighed into a scintillationvial, and the vial was put on horizontal roller mixer to roll overnightbefore injection.

Plasma SPE Extraction Procedure for Active Risperidone Plasma Analysis

This procedure was adopted from Price, M., Hoffman, D., Therapeutic DrugMonitoring, 19, 333-337 (1997). Bond Elute Certify LRC solid-phaseextraction columns were prepared by washing with 6 mL methanol andconditioned with 3 mL 0.1 M sodium phosphate buffer (pH 6).Approximately 1 mL of plasma was loaded onto the wet columns and allowedto filter without vacuum. The columns were washed with 3 mL 1 M aceticacid by pulling vacuum and dried for 5 minutes under vacuum. The columnswere washed with 6 mL methanol at low vacuum and dried for about 2minutes under full vacuum.

The samples were eluted into test tubes with about 2 mL of 3% ammoniumhydroxide in ethyl acetate using gravity filtration. The reagent wasmade fresh daily and sonicated before use. The elutes were evaporated todryness at 42° C. under a stream of nitrogen gas. The residue wasdissolved in 150 μL of 65/35 ammonium acetate/acetonitrile, pH 5.4 byvortexing and shaking on the rotary shaker at about 250 rpm at roomtemperature for about 10 minutes. An aliquot of the solution was placedin an High Performance Liquid Chromatography vial for High PerformanceLiquid Chromatography analysis. The sample was analyzed by risperidoneHigh Performance Liquid Chromatography method described below.

Reversed Phase High Performance Liquid Chromatography Method for theQuantization of Risperidone and 9-Hydroxy-Risperidone

The High Performance Liquid Chromatography had the following conditions:Mobile Phase: 35:65 acetonitrile: ammonium acetate, pH 5.4; flow rate:1.5 ml/min; autosampler temperature: room temperature; columntemperature: room temperature; detection: 275 nm (UV); total run time: 8min; injection volume: 20 μL; column: Phenomenex Luna C18 250×4.6 mm, 5μm; column storage: 70/30 acetonitrile/water; approximate retention timeof risperidone: 3 minutes; and approximate retention time of9-hydroxyrisperidone: 2.4 minutes.

For about 2 liters of 35:65 actonitrile:ammonium acetate, pH 5.4 mobilephase, add about 2.5 g ammonium acetate to 1300 mL of H₂O, add 700 mL ofacetonitrile, mix to dissolve solids, adjust pH to 5.4±0.1 by addingglacial acetic acid, monitor pH with a calibrated electrode, and degasby sonicating the solution for about 5 minutes.

The standard solution preparation is as follows: standard stock solutionwas made by dissolving approximately 10 mg risperidone in 10 mL 1:1acetonitrile/H₂O. A series standards ranging from 10 ppm to 800 ppm wasdiluted with 1:1 acetonitrile/H₂O from the standard stock solution.

Implant Extraction Procedure for Implant Retrieval Study

The retrieved implants and tissue were placed in a −86° C. freezer forat least 1 hour. The frozen samples were lyophilized for at least 4hours. The dry samples were minced with scissors, which were cleanedafter each sample to minimize cross-contamination. The samples wereminced until powder-like. Approximately 5 mL of 70:30dimethylsulfoxide/methanol with 1% polyethyleneimine extraction solventwas added to each sample. The samples were mixed overnight at about 200rpm at 37° C. on the orbital shaker. The samples were sonicated for 10minutes. 1.5 mL of the extract was loaded into a 3 mL lure lock syringeand filtered through a 0.2 μm pore size filter into a clean test tube. 1mL of the filtrate was placed into a clean test tube and 4 mL of 50:50acetonitrile/H₂O was added. The test tube was vortexed for 30 seconds.About 2 mL of the solution was loaded into a 3 mL lure lock syringe andfiltered into an High Performance Liquid Chromatography vial. Thesolution was analyzed by the risperidone High Performance LiquidChromatography method.

Example 1 Risperidone Release Kinetics and Pharmacokinetics Studies inRats

Experimental Procedures

All rat preclinical studies were conducted in Sprague-Dawley rats. Fiverats per Test Article per time point were injected eitherintramuscularly or subcutaneously under full anesthesia in the dorsalthoracic (DT) region with approximately 100 mg of the Test Article,described above.

During the course of the study, the animals were observed for overttoxicity and any existing test site abnormalities, including redness,bleeding, swelling, discharge, bruising and Test Article extrusion atthe injection site were observed and recorded. In addition, injectionweights were recorded at administration and body weights were taken andrecorded at administration and at termination.

At selected time points, five rats per Test Article were anesthetizedand bled (about 5 mL) via cardiac puncture. Blood was collected inlabeled potassium ethylenediaminetetraacetic acid tubes. The blood wascentrifuged for 10 min at 3000 rpm. The plasma fraction was transferredto labeled 5 mL plastic culture tubes and stored at −86° C. The plasmawas extracted following the Plasma SPE Extraction Procedure For ActiveRisperidone Plasma Analysis, described above.

The active risperidone concentrations were analyzed using the ReversedPhase High Performance Liquid Chromatography Method For The Quantizationof Risperidone And 9-Hydroxyrisperidone, described above.

The active risperidone plasma concentration was calculated based on bothrisperidone and 9-hydroxyrisperidone. Since 9-hydroxyrisperidone, theproduct of biotransformation of risperidone in the liver, has the samepharmacological activity and intensity as parent risperidone, it istypical to combine these two risperidone compounds when monitoring theantischizophrenic therapy of risperidone administration.

After blood collection, the animals were terminated with carbon dioxideand the implants were retrieved. The implants were frozen at −86° C. andlyophilized at least 4 hours. The dried implants were extractedfollowing the implant extraction procedure (see the Implant ExtractionProcedure for Implant Retrieval Study, described above), and therisperidone content was analyzed using the Reversed Phase HighPerformance Liquid Chromatography Method for the Quantization ofRisperidone and 9-Hydroxyrisperidone, described above.

Results and Discussion for the 24-Hour Burst Studies

The initial 24-hour risperidone release or burst, from the ATRIGEL®delivery system was of interest to the development program. Eight24-hour in vivo release studies were performed in rats to ensure controlof the burst from the system and to identify formulations that couldpossibly result in sustained risperidone release for 28-days.

The first 24-hour in vivo release study (EXAMPLE 1.1) was conductedusing risperidone freebase and was designed to investigate the role ofpolymer concentration, polymer inherent viscosity and lactide toglycolide ratio within the polymer. The initial release was founddependent on the polymer concentration (the higher the concentration thelower the risperidone burst), inherent viscosity of the polymer (thehigher the inherent viscosity the lower the burst), and the lactide toglycolide ratio (the higher the lactide ratio the lower the burst). Thedifferences between the acid end group and the methyl end group wereminor and within standard deviation. This study resulted inidentification of ATRIGEL® vehicle containing approximately 40% 50/50PLGH (InV 0.36) in N-methyl-2-pyrrolidone as possible candidate forfurther evaluation. See Table 1.

TABLE 1 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone Wt. % Form- Injected Remaining in RisperidoneAVG. Wt. % ulation (mg) Implant (mg) Released Released Group I- 10%Risperidone in 50% 50/50 PLGH (InV 0.18) and 50% NMP 12.88 10.76 16.4112.39 11.20 9.64 11.85 10.06 15.14 14.69 ± 2.98  13.01 11.06 14.97 11.509.51 17.29 Group II- 10% Risperidone in 45% 50/50 PLGH (InV 0.18) and55% NMP 12.32 10.90 11.56 12.64 5.77 54.35 12.23 10.48 14.30 36.01 ±21.97 11.90 4.97 58.24 12.14 7.09 41.58 Group III- 10% Risperidone in40% 50/50 PLGH (InV 0.36) and 60% NMP 10.97 9.21 16.04 11.20 10.50 6.3312.55 11.84 5.66 6.55 ± 5.71 11.87 11.76 0.91 11.77 11.32 3.81 Group IV-10% Risperidone in 37% 50/50 PLGH (InV 0.36) and 63% NMP 11.01 9.8210.79 11.89 10.50 11.73 11.72 10.78 8.05 8.21 ± 3.79 12.25 12.01 2.0210.95 10.02 8.48 Group V- 10% Risperidone in 50% 65/35 PLGH (InV 0.20)and 50% NMP 12.26 7.72 37.02 11.69 8.34 28.61 12.28 5.99 51.18 31.13 ±13.47 12.15 9.55 21.42 11.62 9.60 17.42 Group VI- 10% Risperidone in 50%75/25 PLGH (InV 0.24) and 50% NMP 12.50 10.43 16.59 11.37 9.94 12.5211.39 10.16 10.77 11.62 ± 3.16  11.53 10.56 8.36 11.72 10.57 9.85 GroupVII- 10% Risperidone in 40% 50/50 PLG (InV 0.18) and 60% NMP 12.41 4.8360.80 11.58 4.94 57.33 12.10 5.91 51.15 53.62 ± 5.19  12.01 6.15 48.7712.37 6.18 50.03 Group VIII- 10% Risperidone in 40% 50/50 PLG (InV 0.35)and 60% NMP 11.25 10.23 9.08 11.41 11.00 3.59 11.96 11.44 4.34 5.02 ±3.05 11.26 11.13 1.18 11.23 10.46 6.89 Group IX- 10% Risperidone in 40%75/25 PLG (InV 0.26) and 60% NMP 11.50 9.97 13.26 11.46 9.75 14.88 11.2410.08 10.24 11.17 ± 3.50  11.40 10.06 11.72 12.45 11.74 5.72

The next three in vivo studies (EXAMPLES 1.2, 1.3, and 1.4) weredesigned to evaluate risperidone salts in the ATRIGEL® delivery system.By forming risperidone salts with anionic counter-ions thephysicochemical properties of risperidone were altered, such as thestability and the solubility in N-methyl-2-pyrrolidone and water.Ultimately helping risperidone to be more compatible with the ATRIGEL®delivery system as well as reducing the burst. Table 2 shows therisperidone salts that were investigated.

TABLE 2 Risperidone salt abbreviation Anion Ratio RSPCl HydrochloricAcid 1:1 RSPCA Citric Acid 1:1 RSP Acetate Acetic Acid 1:1 RSP TartrateTartaric Acid 1:1 RSP Pamoate Pamoic Acid 1:1 RSP Naphthoate NaphthoicAcid 1:1 RSP DOS Dioctylsulfosuccinate 1:1

These salts were investigated using the same or similar ATRIGEL®vehicles identified in EXAMPLE 1.1 (approximately 40% 50/50 PLGH (InV0.36) in N-methyl-2-pyrrolidone). The 24-hour release of these saltsranged from 17 to 78% of the total risperidone in the ATRIGEL®formulation (See Tables 3-5). The pamoate and citrate salt showed themost promise of all the salts investigated, however none of therisperidone salts met the requirement of approximately 10% burst.

TABLE 3 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. RSP Wt.% Form- Wt. RSP salt Remaining in RSP AVG. Wt. % ulation Injected (mg)Implant (mg) Released Released Group I- 10% RSPCl in 40% 50/50 PLGH (InV0.36) and 60% NMP 9.58 3.98 58.45 9.13 2.93 67.87 11.19 3.74 66.62 67.91± 6.23 11.73 2.93 75.02 11.72 3.33 71.59 Group II- 10% RSPCl in 37%50/50 PLGH (InV 0.36) and 63% NMP 8.32 1.46 82.45 11.17 3.16 71.76 10.432.30 77.91 78.46 ± 4.11 11.35 2.17 80.88 10.64 2.21 79.28 Group III- 10%RSPCl in 50% 75/25 PLGH (InV 0.15) and 50% NMP 13.51 4.69 65.33 11.013.06 72.17 11.03 3.08 72.05 69.38 ± 3.24 12.15 2.54 70.90 12.46 4.1866.47 Group IV- 10% RSPCl in 40% 75/25 PLGH (InV 0.24) and 60% NMP 12.302.71 78.00 9.71 1.97 79.69 11.12 2.43 78.15 74.98 ± 5.08 10.87 3.4368.41 10.95 3.22 70.64 Group V- 10% RSPCl in 34% 50/50 PLGH (InV 0.47)and 66% NMP 6.29 0.89 85.90 8.86 0.97 89.07 10.41 1.45 86.07 85.88 ±2.11 10.90 1.83 83.24 11.46 1.71 85.12 Group VI- 10% RSPCA in 37% 50/50PLGH (InV 0.36) and 63% NMP 9.46 6.00 36.61 9.76 4.99 48.87 11.19 8.6522.65  30.03 ± 12.51 11.77 9.03 23.27 11.45 9.30 18.75 Group VII- 20%RSPCl in 37% 50/50 PLGH (InV 0.36) and 63% NMP 9.08 1.25 86.20 10.081.80 82.13 11.78 0.91 92.32 87.72 ± 4.23 14.55 1.99 86.35 12.22 1.0391.58 Group VIII- 20% RSPCl in 30% 50/50 PLGH (InV 0.36) and 70% NMP10.27 1.10 89.26 12.33 1.01 91.80 9.43 0.37 86.08 93.49 ± 3.01 10.070.62 93.80 8.94 0.31 96.49

TABLE 4 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone Wt. % Form- salt Remaining in Risperidone AVG.Wt. % ulation Injected (mg) Implant (mg) Released Released Group I- 10%RSPAcetate in 37% 50/50 PLGH (InV 0.36) and 63% NMP 8.81 5.14 41.7312.16 6.88 43.44 8.73 4.21 51.78 40.69 ± 7.88 11.79 7.68 34.92 12.348.45 31.57 Group II- 10% RSPTartrate in 37% 50/50 PLGH (InV 0.36) and63% NMP 10.38 3.74 63.96 7.97 3.41 57.17 8.96 3.65 59.28 59.87 ± 2.579.12 3.61 60.37 9.90 4.06 58.56 Group III- 10% RSPCA Encapsulated inMannitol (Cast and Grind) in 37% 50/50 PLGH (InV0.36) and 63% NMP 10.295.39 47.57 8.19 3.50 57.29 10.20 5.55 45.57 47.63 ± 6.97 9.79 6.07 38.0210.19 5.12 49.71 Group IV- 10% RSPCA Encapsulated in Mannitol(Lypholized) in 37% 50/50 PLGH (InV 0.36) and 63% NMP 8.01 4.29 46.419.53 4.27 55.18 10.95 5.58 49.06 47.85 ± 4.54 12.27 6.82 44.46 11.566.46 44.16 Group V- 10% RSPCA in 37% 50/50 PLGH (InV 0.18) and 63% NMP12.11 2.18 81.97 10.78 2.59 75.95 9.27 4.22 54.45 72.66 ± 15.52 9.360.79 91.56 11.38 4.63 59.36 Group VI- 10% RSPCA in 34% 65/35 PLGH (InV0.19) and 66% NMP 10.71 3.23 69.81 10.31 2.79 72.91 12.13 1.71 85.8977.99 ± 6.65 10.92 2.32 78.72 10.53 1.83 82.60 Group VII- 10% RSPCA in34% 75/25 PLGH (InV 0.24) and 66% NMP 12.43 3.36 72.97 8.96 2.56 71.4112.31 2.40 80.53 72.86 ± 4.57 11.23 3.27 70.86 11.23 3.53 68.53 GroupVIII- 10% RSPCA in 34% 85/15 PLGH (InV 0.25) and 66% NMP 10.83 3.3069.49 11.32 3.90 65.56 10.35 3.46 66.56  72.44 ± 11.10 11.10 0.88 92.1110.87 3.42 68.50

TABLE 5 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone Wt. % Form- salt Remaining in Risperidone AVG.Wt. % ulation Injected (mg) Implant (mg) Released Released Group I- 10%RSP in 37% 50/50 PLGH (InV 0.36) and 63% NMP 10.68 8.89 16.79 11.77 9.9515.48 10.65 8.19 23.10 20.27 ± 4.01 10.84 8.15 24.80 10.43 8.22 21.18Group II- 10% RSP DOS in 37% 50/50 PLGH (InV 0.36) and 63% NMP 10.398.60 17.19 9.33 6.61 29.19 13.92 9.16 34.19 29.81 ± 7.39 10.23 6.7833.72 8.12 5.30 34.76 Group III- 10% RSP Naphthoate in 37% 50/50 PLGH(InV 0.36) and 63% NMP 8.31 5.10 38.67 9.29 5.82 37.29 11.95 6.36 46.7940.42 ± 4.21 10.89 6.88 36.83 10.53 6.05 42.54 Group IV- 10% RSP Pamoatein 37% 50/50 PLGH (InV 0.36) and 63% NMP 10.64 8.94 16.02 11.05 8.2825.04 8.07 6.32 21.72 17.17 ± 8.54 12.17 11.80 3.05 11.16 8.92 20.01Group V- 10% RSPCA/Cholesterol (1:1) in 37% 50/50 PLGH (InV 0.36) and63% NMP 8.87 3.38 61.87 10.12 3.86 61.88 8.93 3.54 60.39 61.28 ± 0.706.94 2.67 61.57 8.24 3.24 60.69 Group VI- 10% RSPCA in 31.5% 50/50 PLGH(InV 0.36) + 5.5% 50/50 PLGH (InV 0.57) and 63% NMP 8.66 6.76 21.9911.08 8.26 25.41 10.95 7.63 30.28 28.61 ± 5.04 13.29 9.27 30.27 12.097.85 35.10 Group VII- 10% RSPCA in 31.5% 50/50 PLGH (InV 0.36) + 5.5%50/50 PLGH (InV 0.49) and 63% NMP 1.04 8.53 29.19 11.96 8.78 26.58 11.387.62 33.00 33.70 ± 9.86 14.16 10.07 28.87 10.79 5.30 50.85 Group VIII-10% RSPCA in 2% PEG + 36% 50/50 PLGH (InV 0.36) and 63% NMP 10.03 5.5944.24 11.02 7.20 34.66 9.03 5.82 35.55 36.04 ± 8.42 9.81 5.62 42.7413.14 10.12 23.02

EXAMPLE 1.5 investigated the addition of excipients to the ATRIGEL®formulation. Excipients such as triethylcitrate, ethylheptanoate, andpolyvinylpyrrolidone were added to the ATRIGEL® delivery system to aidin the burst control of risperidone from the ATRIGEL® system. Theresults of this study indicate that the addition of these excipients didnot help control the burst of risperidone to less than 10% (See Table6).

TABLE 6 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone salt Remaining Wt. % Injected in RisperidoneAVG. Wt. % Formulation (mg) Implant (mg) Released Released Group I: 20%Risperidone in 37% 50/50 PLGH (InV 0.36) and 63% NMP 24.37 20.07 17.6426.09 23.10 11.46 19.79 17.46 11.78 13.89 ± 3.79  19.59 17.58 10.2522.15 18.09 18.33 Group II: 10% Risperidone in 44% 50/50 PLGH (InV 0.36)and 56% NMP 15.94 7.41 53.48 7.87 4.51 42.71 11.00 7.57 31.15 37.00 ±22.52 9.96 4.31 56.73 9.64 9.55 0.94 Group III: 10% Risperidone in 37%50/50 PLGH (InV 0.36) and 63% NMP 15.26 12.01 21.30 10.07 7.79 22.6510.18 6.55 35.64 18.65 ± 12.57 11.20 9.93 11.33 11.76 11.49 2.31 GroupIV: 10% Risperidone in 37% 50/50 PLGH (InV 0.36) and 63% NMP [Prep'd 1hr prior to dosing] 11.26 9.76 13.30 10.60 9.19 13.34 10.11 8.64 14.5118.05 ± 7.43  9.37 7.66 18.26 11.65 8.06 30.84 Group V: 10% Risperidoneand 5% triethyl citrate in 37% 50/50 PLGH (InV 0.36) and 63% NMP 10.576.39 39.57 9.79 4.01 59.07 9.93 7.12 28.27 33.30 ± 17.20 10.33 7.6026.47 10.28 8.93 13.11 Group VI: 10% Risperidone and 5% ethyl heptanoatein 37% 50/50 PLGH (InV 0.36) and 63% NMP 9.13 6.73 26.25 8.28 5.80 29.9510.08 7.62 24.37 28.24 ± 8.70  9.72 5.64 41.98 10.62 8.64 18.66 GroupVII: 10% Risperidone and 5% polyvinyl pyrrolidone (PVP) C15 in 37% 50/50PLGH (InV 0.36) and 63% NMP 9.95 6.96 30.06 8.46 5.32 37.06 11.49 8.1129.47 27.99 ± 6.55  9.92 7.65 22.91 9.76 7.77 20.44 Group VIII: 10%Risperidone and 3% PVP C30 in 37% 50/50 PLGH (InV 0.36) and 63% NMP 9.667.81 19.23 11.73 9.09 22.53 10.96 8.32 24.04 26.78 ± 15.09 9.76 8.3015.05 10.91 5.12 53.06 Group IX: 10% RSPCA and 10% triethyl citrate in37% 50/50 PLGH (InV 0.36) and 63% NMP 9.45 3.98 57.90 9.75 4.79 50.8213.70 4.62 66.30 54.88 ± 7.71  10.24 4.76 53.47 11.27 6.09 45.94 GroupX: 10% Risperidone and 10% ethyl heptanoate in 37% 50/50 PLGH (InV 0.36)and 63% NMP 8.83 5.83 33.94 10.14 5.55 45.23 11.68 7.59 35.06 38.18 ±4.56  10.46 6.62 36.69 11.11 6.67 40.00 Group XI: 10% RSP pamoate (1:1)in 37% 50/50 PLGH (InV 0.36) and 63% NMP 9.28 4.85 47.80 9.72 5.49 43.5110.08 5.85 42.02 39.64 ± 12.96 11.43 5.95 47.93 10.63 8.83 16.93 GroupXII: 10% RSP pamoate (2:1) and 10% ethyl heptanoate in 37% 50/50 PLGH(InV 0.36) and 63% NMP 9.68 4.92 49.20 10.06 4.40 56.31 11.50 5.55 51.7354.51 ± 10.78 11.75 3.30 71.90 10.46 5.92 43.41

EXAMPLES 1.6 and 1.7 investigated the risperidone freebase without theformation of salts or the addition of excipients administratedsubcutaneously. The test articles were selected to again evaluate theeffect of polymer concentration, inherent viscosity, and lactide toglycolide ratio. The results of this study agreed well with EXAMPLE 1.1study results. ATRIGEL® formulations consisting of (1) 40% 50/50 PLGH(InV 0.36) and 60% N-methyl-2-pyrrolidone, (2) 40% 50/50poly(lactide-co-glycolide) (InV 0.19) and 60% N-methyl-2-pyrrolidone,(3) 40% 50/50 poly(lactide-co-glycolide) (InV 0.33) and 60%N-methyl-2-pyrrolidone, or (4) 40% 65/35 PLGH (InV 0.37) and 60%N-methyl-2-pyrrolidone were found to control the burst of risperidone toapproximately 10%. The release of risperidone from ATRIGEL® formulationsof EXAMPLES 1.6 and 1.7 are illustrated in FIGS. 1 and 2. The detailedrisperidone release data and active plasma concentrations are listed inTables 7-8 for EXAMPLE 1.6, and in Tables 9-10 for EXAMPLE 1.7.

TABLE 7 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone salt Remaining Wt. % Injected in RisperidoneAVG. Wt. % Formulation (mg) Implant (mg) Released Released Group I: 10%Risperidone in 40% 50/50 PLGH (InV 0.36) and 60% NMP (A/B Mixed) 13.7213.89 −1.26 10.08 9.71 3.72 9.23 8.62 6.62 4.89 ± 4.69 11.18 9.89 11.5614.11 13.58 3.80 Group II: 10% Risperidone in 40% 50/50 PLGH (InV 0.36)and 60% NMP (Roll Mixed) 18.30 17.05 6.80 15.34 14.20 7.47 12.79 11.907.01 7.13 ± 0.38 12.45 11.61 6.79 14.39 13.30 7.59 Group III: 10%Risperidone in 40% 50/50 PLG (InV 0.19) and 60% NMP (A/B Mixed) 10.269.65 5.98 9.60 8.84 7.96 11.36 5.10 55.08 9.05 ± 2.91 10.42 9.44 9.3910.72 9.34 12.88 Group IV: 10% Risperidone in 40% 50/50 PLG (InV 0.19)and 60% NMP (Roll Mixed) 12.97 11.71 9.70 15.84 14.74 6.94 12.58 11.0811.93 9.79 ± 1.94 15.50 13.76 11.20 13.07 11.87 9.19 Group V: 10%Risperidone in 40% 50/50 PLG (InV 0.33) and 60% NMP (A/B Mixed) 12.2011.30 7.38 6.49 5.79 10.79 8.55 7.31 14.49 9.11 ± 3.53 11.20 10.41 7.0711.09 10.44 5.82 Group VI: 10% Risperidone in 40% 75/25 PLG (InV 0.19)and 60% NMP (A/B Mixed) 10.06 8.31 17.42 9.90 8.85 10.59 11.09 9.8511.18 13.33 ± 2.92  13.01 11.02 15.28 11.42 10.03 12.16 Group VII: 10%Risperidone in 50% 50/50 PLGH (InV 0.18) and 50% NMP (A/B Mixed) 15.9314.04 11.84 10.97 9.88 9.92 9.44 7.76 17.76 12.45 ± 3.20  12.52 10.9212.74 12.56 11.30 9.99 Group VIII: 10% Risperidone in 50% 65/35 PLGH(InV 0.20) and 50% NMP (A/B Mixed) 16.99 11.11 34.60 8.60 6.09 29.1510.35 7.19 30.48 30.28 ± 2.65  11.75 8.52 27.51 12.00 8.44 29.67 GroupIX: 10% Risperidone in 50% 75/25 PLGH (InV 0.15) and 50% NMP (A/B Mixed)14.18 9.43 33.51 12.62 8.77 30.52 11.79 8.51 27.86 30.13 ± 2.72  9.106.21 31.80 11.42 8.34 26.97 Group X: 10% Risperidone in 30% 50/50 PLGH(InV 0.30), 15% 85/15 PLGH (InV 0.27) and 50% NMP (A/B Mixed) 13.3712.03 10.06 11.08 10.19 8.05 9.80 8.74 10.74 11.19 ± 2.49  9.74 8.3214.64 10.47 9.17 12.45

TABLE 8 24-Hour Active Risperidone Plasma Concentrations Total PlasmaMean Plasma Concentration Concentration Standard Formulation (ng/ml)(ng/ml) Deviation Group I: 10% Risperidone in 40% 50/50 PLGH (InV 0.36)and 60% NMP (A/B Mixed) 65.1 48.4 48.5 59.0 12.6 55.2 77.9 Group II: 10%Risperidone in 40% 50/50 PLGH (InV 0.36) and 60% NMP (Roll Mixed) 39.063.2 43.2 48.8 9.2 49.2 49.4 Group III: 10% Risperidone in 40% 50/50 PLG(InV 0.19) and 60% NMP (A/B Mixed) 83.6 70.1 97.5 82.4 13.3 93.0 68.0Group IV: 10% Risperidone in 40% 50/50 PLG (InV 0.19) and 60% NMP (RollMixed) 70.7 74.6 64.5 68.0 5.1 68.2 61.7 Group V: 10% Risperidone in 40%50/50 PLG (InV 0.33) and 60% NMP (A/B Mixed) 64.2 49.1 42.8 55.9 12.072.1 51.4 Group VI: 10% Risperidone in 40% 75/25 PLG (InV 0.19) and 60%NMP (A/B Mixed) 102.0 68.3 119.3 89.7 20.6 79.0 79.7 Group VII: 10%Risperidone in 50% 50/50 PLGH (InV 0.18) and 50% NMP (A/B Mixed) 126.791.3 157.5 122.2 29.9 143.4 92.3 Group VIII: 10% Risperidone in 50%65/35 PLGH (InV 0.20) and 50% NMP (A/B Mixed) 521.3 139.3 163.3 246.3173.0 309.2 98.6 Group IX: 10% Risperidone in 50% 75/25 PLGH (InV 0.15)and 50% NMP (A/B Mixed) 161.4 117.7 162.6 148.6 25.9 176.9 124.6 GroupX: 10% Risperidone in 30% 50/50 PLGH (InV 0.30), 15% 85/15 PLGH (InV0.27) and 50% NMP (A/B Mixed) 69.9 41.6 40.7 58.7 20.1 53.7 87.7

TABLE 9 24-Hour Risperidone Release From ATRIGEL ® Implants Wt. Wt.Risperidone Risperidone Remaining Wt. % salt Injected in RisperidoneAVG. Wt. % Formulation (mg) Implant (mg) Released Released Group I: 10%Risperidone in 40% 50/50 PLGH (InV 0.36) and 60% NMP 7.51 6.20 17.4410.19 9.26 9.15 11.80 11.22 4.90 8.96 ± 5.03 10.70 10.10 5.64 13.7412.69 7.69 Group II: 10% Risperidone in 40% 50/50 PLGH (InV 0.45) and56% NMP 15.60 8.59 44.97 9.27 4.90 47.15 10.13 6.39 36.92 28.64 ± 20.3013.30 11.76 11.62 11.17 10.88 2.53 Group III: 10% Risperidone in 35%50/50 PLGH (InV 0.45) and 65% NMP 10.92 9.60 12.09 13.26 12.41 6.3810.40 8.16 21.49 12.93 ± 4.87  13.02 10.85 16.68 17.47 14.57 16.58 GroupIV: 10% Risperidone in 45% 50/50 PLGH (InV 0.36) and 55% NMP 8.10 7.2510.43 13.40 12.30 8.20 11.11 9.16 17.58 12.79 ± 4.56  11.74 9.64 17.8311.95 10.77 9.92 Group V: 10% Risperidone in 40% 65/35 PLGH (InV 0.37)and 60% NMP 10.06 9.35 7.10 12.53 11.70 6.60 11.59 10.81 6.72 8.48 ±2.47 13.17 11.55 12.28 16.71 15.09 9.71 Group VI: 10% Risperidone in 45%65/35 PLGH (InV 0.37) and 55% NMP 13.07 10.27 21.42 12.47 7.66 38.5912.62 7.60 39.74 15.25 ± 25.93 15.14 16.19 −6.88 13.14 15.33 −16.63Group VII: 10% Risperidone in 40% 75/25 PLGH (InV 0.45) and 60% NMP 8.716.16 29.31 13.01 9.18 29.41 9.02 6.75 25.20 21.95 ± 9.25  10.47 8.5518.32 10.81 10.00 7.50 Group VIII: 10% Risperidone in 45% 75/25 PLGH(InV 0.45) and 55% NMP 9.10 5.76 36.66 11.49 9.93 13.57 11.56 8.91 22.9615.60 ± 14.75 12.69 11.99 5.52 13.48 13.58 −0.74

TABLE 10 24-Hour Active Risperidone Plasma Concentrations Total PlasmaMean Plasma Concentration Concentration Standard Formulation (ng/ml)(ng/ml) Deviation Group I: 10% Risperidone in 40% 50/50 PLGH (InV 0.36)and 60% NMP 90.9 66.3 65.7 78.9 12.2 82.9 88.9 89.3 Group II: 10%Risperidone in 40% 50/50 PLGH (InV 0.45) and 56% NMP 89.3 74.8 82.1 85.17.7 84.2 95.2 Group III: 10% Risperidone in 35% 50/50 PLGH (InV 0.45)and 65% NMP 82.3 80.6 106.3  82.7 14.0 70.3 74.2 Group IV: 10%Risperidone in 45% 50/50 PLGH (InV 0.36) and 55% NMP 69.1 55.9 52.5 57.36.8 52.5 56.2 Group V: 10% Risperidone in 40% 65/35 PLGH (InV 0.37) and60% NMP 110.4  113.8  59.8 91.9 23.3 99.7 75.8 Group VI: 10% Risperidonein 45% 65/35 PLGH (InV 0.37) and 55% NMP 62.5 79.8 70.4 71.6 7.5 66.978.7 Group VII: 10% Risperidone in 40% 75/25 PLGH (InV 0.45) and 60% NMP85.2 95.1 74.2 88.0 10.6 Not available 97.3 Group VIII: 10% Risperidonein 45% 75/25 PLGH (InV 0.45) and 55% NMP 95.6 80.6 113.9  96.2 15.1108.7  82.2

The final 24-hour in vivo study (EXAMPLES 1.8) investigated the affectof risperidone loading on the release of risperidone. Risperidone wasevaluated at about 15% and about 20% weight percentage. It was foundthat the weight % of risperidone in the formulation had a significantaffect on the 24-hour release (See Table 11). From the eight 24-hour invivo studies conducted several risperidone/ATRIGEL® formulations wereidentified for further evaluation over a period of 28-days in the rat.

TABLE 11 24-Hour Risperidone Release From ATRIGEL ® Implants Wt.Risperidone Wt. Risperidone Wt. % Formu- salt Injected Remaining inRisperidone AVG. Wt. % lation (mg) Implant (mg) Released Released GroupI: 15% Risperidone in 38% 65/35 PLGH 0.37, 2% 70/30 PLG/PEG5000 0.79 and60% NMP 15.24 13.64 10.45 14.22 13.74 3.40 16.91 15.02 11.21 6.37 ± 4.8617.86 16.59 7.14 17.91 17.97 −0.32 Group II: 20% Risperidone in 38%65/35 PLGH 0.37, 2% 70/30 PLG/PEG5000 0.79 and 60% NMP 13.96 12.31 11.8032.75 28.86 11.87 20.83 19.47 6.54 7.33 ± 6.03 22.19 22.40 −0.91 27.6428.86 −4.42Results and Discussion for the 28-Day Rat Studies

Six 28-Day and one 14-Day rat studies were conducted to evaluate therelease of risperidone from ATRIGEL® delivery systems. All formulationswere injected into rats subcutaneously. The composition of each testarticle is summarized in Table 12. Review of these studies indicates anumber of findings: Risperidone was stable in ATRIGEL® implants for 28days. Risperidone plasma levels were detectable up to 28 days in therat. Two lead formulations consisting of 15% (w/w) risperidone suspendedin two ATRIGEL® composition were identified. The two ATRIGEL®compositions are: (1) 45% 65/35 PLGH (InV=0.37 dL/g) and 55%N-methyl-2-pyrrolidone; (2) 25% 85/15 PLGH (InV 0.27 dL/g), 20% 50/50PLGH (InV 0.36 dL/g) and 55% N-methyl-2-pyrrolidone. These twoformulations provided an initial burst of about 10% and nearlyzero-order release of risperidone over 28 days based on implantretrieval data. The pharmacokinetic profiles of all Test Articles showedmaximum active risperidone plasma levels at 24-hours post dosing, anddecreased slowly until Day 28. The plasma active risperidone levels ofthe two lead formulations remained higher than 15 ng/ml at Day 28. Thearea under the curve from Day 0 to Day 28 (AUC_(Day 0-28)) wasproportional to risperidone dosage.

TABLE 12 Summary of 28-Day Risperidone Rat Studies Study Study #duration Test Article EXAMPLE 28 Days 1. 10% Risperidone suspended in40% 50/50 1.9 PLGH (InV 0.36) and 60% NMP 2. 10% Risperidone suspendedin 35% 50/50 PLGH (InV 0.45) and 65% NMP 3. 10% Risperidone suspended in40% 65/35 PLGH (InV 0.37) and 60% NMP 4. 10% Risperidone suspended in38% 50/50 PLGH (InV 0.36), 2% 70/30 PLG/PEG5000 (InV 0.79) and 60% NMP5. 10% Risperidone suspended in 33% 50/50 PLGH (InV 0.45), 2% 70/30PLG/PEG5000 (InV 0.79) and 65% NMP 6. 10% Risperidone suspended in 38%65/35 PLGH (InV 0.37), 2% 70/30 PLG/PEG5000 (InV 0.79) and 60% NMPEXAMPLE 28 Days 1. 10% Risperidone suspended in 38% 65/35 1.10 PLGH (InV0.37), 2% PEG300 and 60% NMP 2. 10% Risperidone suspended in 35% 65/35PLGH (InV 0.37), 5% PEG300 and 60% NMP 3. 10% Risperidone suspended in35% 65/35 PLGH (InV 0.37), 5% 70/30 PLG/PEG5000 (InV 0.79) and 60% NMP4. 10% Risperidone suspended in 40% 75/25 PLGH (InV 0.45) and 60% NMP 5.10% Risperidone suspended in 38% 75/25 PLGH (InV 0.45), 2% 70/30PLG/PEG5000 (InV 0.79) and 60% NMP 6. 10% Risperidone suspended in 40%85/15 PLGH (InV 0.27) and 60% NMP EXAMPLE 28 Days 1. 10% Risperidonesuspended in 40% 65/35 1.11 PLGH (InV 0.37) and 60% NMP 2. 20%Risperidone suspended in 40% 65/35 PLGH (InV 0.37) and 60% NMP 3. 25%Risperidone suspended in 40% 65/35 PLGH (InV 0.37) and 60% NMP 4. 20%Risperidone suspended in 40% 50/50 PLG (InV 0.33) and 60% NMP 5. 25%Risperidone suspended in 40% 50/50 PLG (InV 0.33) and 60% NMP EXAMPLE 14Days 1. 15% Risperidone suspended in 38% 65/35 1.12 PLGH (InV 0.37) and62% NMP 2. 15% Risperidone suspended in 40% 65/35 PLGH (InV 0.37) and60% NMP 3. 15% Risperidone suspended in 42.5% 65/35 PLGH (InV 0.37) and57.5% NMP 4. 15% Risperidone suspended in 45% 65/35 PLGH (InV 0.37) and55% NMP 5. 15% Risperidone suspended in 45% 75/25 PLGH (InV 0.24) and55% NMP 6. 15% Risperidone suspended in 20% 85/15 PLGH (InV 0.29), 20%50/50 PLGH (InV 0.36) and 60% NMP 7. 15% Risperidone suspended in 40%65/35 PLGH (InV 0.37), 5% PEG8000-PLG and 55% NMP 8. 15% Risperidonesuspended in 22.2% 85/15 PLGH (InV 0.27), 17.8% 65/35 PLGH (InV 0.37)and 60% NMP EXAMPLE 28 Days 1. 15% Risperidone suspended in 40% 65/351.13 PLGH (InV 0.37) and 60% NMP 2. 20% Risperidone suspended in 40%65/35 PLGH (InV 0.37) and 60% NMP 3. 15% Risperidone suspended in 45%65/35 PLGH (InV 0.37) and 55% NMP 4. 20% Risperidone suspended in 45%65/35 PLGH (InV 0.37) and 55% NMP 5. 20% Risperidone suspended in 20%85/15 PLGH (InV 0.27), 20% 50/50 PLGH (InV 0.36) and 60% NMP

Example 1.9

The 28-Day release kinetics and pharmacokinetics of sixATRIGEL®/risperidone formulations containing 10% risperidone weredetermined in this study. Six ATRIGEL® delivery vehicles prepared withdifferent polymers were compared. The implant retrieval results aresummarized in Table 13 and the release profiles are depicted in FIG. 3.The mean active risperidone plasma concentrations are provided in Table14 and illustrated in FIG. 4.

TABLE 13 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 10%Day 1 19.0 12.1 4.0 Risperidone in 40% 50/50 10.7 PLGH (InV 0.36)/60%NMP 9.4 12.0 9.5 Day 7 56.1 59.1 7.6 61.8 62.6 47.6 67.3 Day 14 89.190.0 3.2 91.4 91.4 93.2 84.8 Day 21 98.8 99.4 0.6 100.1 99.0 99.1 100.1Day 28 100.0 100.0 0.0 100.0 100.0 100.0 100.0 Group II: 10% Day 1 18.412.3 3.6 Risperidone in 35%50/50 PLGH 11.4 (InV 0.45)/65% NMP 8.9 11.710.9 Day 7 45.0 47.7 4.1 52.4 49.0 50.1 42.1 Day 14 85.1 86.8 1.1 86.287.5 87.8 87.3 Day 21 97.3 95.2 2.5 96.5 97.1 91.5 93.8 Day 28 100.0100.0 0.0 100.0 100.0 100.0 100.0 Group III: 10% Day 1 22.3 11.8 7.1Risperidone in 40% 65/35 PLGH 12.3 (InV 0.37)/60% NMP 8.1 13.2 3.0 Day 757.1 42.2 8.6 41.4 35.8 38.1 38.7 Day 14 69.1 73.0 3.2 76.5 72.0 76.071.7 Day 21 89.0 88.1 3.6 86.5 87.3 93.7 84.1 Day 28 93.6 96.0 3.6 100.091.1 97.3 98.0 Group IV: 10% Risperidone Day 1 16.4 8.3 4.9 in 38% 50/50PLGH (InV 0.36) + 6.1 20% 70/30 PLG/PEG5000 7.3 (InV 0.79)/60% NMP 8.33.3 Day 7 58.0 57.8 3.9 64.1 54.2 57.7 54.8 Day 14 93.2 89.0 2.6 89.087.5 86.2 89.1 Day 21 98.5 97.2 1.9 93.9 98.2 97.2 98.3 Day 28 100.0100.0 0.0 100.0 100.0 100.0 100.0 Group V: 10% Risperidone Day 1 10.75.2 4.2 in 33% 50/50 PLGH (InV 0.45) + 7.3 2% 70/30 PLG/PEG5000 (InV0.79)/ 4.4 65% NMP 4.4 −0.8 Day 7 48.8 49.7 4.5 43.9 54.4 47.3 54.2 Day14 85.0 85.2 3.3 89.5 84.9 86.0 80.4 Day 21 92.9 96.5 2.2 96.0 98.1 96.998.6 Day 28 100.0 100.0 0.0 100.0 100.0 100.0 100.0 Group VI: 10% Day 1−26.8 7.7 18.0 Risperidone in 38% 65/35 PLGH (InV 0.37) + −29.0 2% 70/30PLG/PEG5000 (InV 6.9 0.79)/60% NMP 8.4 −4.5 Day 7 43.8 37.5 12.5 56.132.4 24.6 30.7 Day 14 63.5 70.7 8.8 84.9 64.8 66.7 73.8 Day 21 87.8 84.82.6 84.1 83.3 81.6 87.1 Day 28 95.1 96.0 2.7 92.7 100.0 95.2 96.9

TABLE 14 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 10% Day 1 40.0 35.5 4.7 Risperidone in 41.2 40%50/50 PLGH (InV 31.7 0.36)/NMP 33.0 31.7 Day 7 75.0 73.9 6.6 81.2 71.478.2 64.0 Day 14 15.1 12.7 4.6 9.6 19.2 7.4 12.3 Day 21 3.5 4.4 2.3 N/A6.3 6.2 1.5 Day 28 3.9 4.0 2.1 2.0 6.2 NDL* NDL* Group II: 10% Day 156.9 46.1 11.0 Risperidone in 54.3 35% 50/50 PLGH (InV 30.6 0.45)/NMP39.1 49.6 Day 7 47.0 49.8 15.0 67.3 28.7 60.7 45.4 Day 14 22.2 22.2 5.527.8 22.4 25.5 13.3 Day 21 12.3 8.4 3.2 7.2 4.7 6.8 11.0 Day 28 5.7 6.23.5 10.0 3.0 NDL* NDL* Group III: 10% Day 1 46.0 49.3 13.1 40% 65/35PLGH 60.8 33.8 64.7 41.4 Day 7 31.7 43.1 14.9 36.5 32.3 47.7 67.2 Day 1430.5 30.1 12.6 18.9 25.7 23.9 51.4 Day 21 7.4 9.9 3.1 14.5 7.3 8.7 11.5Day 28 17.2 10.4 5.2 3.6 12.9 10.7 7.6 Group IV: 10% Day 1 29.9 34.5 5.550/50 PLGH (InV 33.2 PLG/PEG5000 (InV 44.0 31.7 34.0 Day 7 64.6 92.743.4 41.8 155.6 94.9 106.4 Day 14 12.2 17.7 5.3 18.9 12.7 24.8 19.9 Day21 1.5 5.6 4.7 5.2 13.3 6.1 2.2 Day 28 3.7 3.7 0 NDL* NDL* NDL* NDL*Group V: 10% Day 1 35.0 40.2 16.8 50/50 PLGH (InV 69.2 PLG/PEG5000 (InV38.8 29.1 28.7 Day 7 55.7 67.7 16.4 47.5 86.3 68.2 80.9 Day 14 21.8 24.46.5 22.9 26.4 16.8 34.3 Day 21 8.0 7.4 4.2 6.1 8.7 12.7 1.3 Day 28 3.23.4 1.5 NDL* NDL* 2.0 5.0 Group VI: 10% Day 1 49.7 36.0 5.6 65/35 PLGH(InV 40.1 70/30 35.8 PLG/PEG5000 (InV 36.2 NMP 39.3 Day 7 28.9 35.9 12.132.3 34.9 26.7 56.9 Day 14 25.0 25.8 7.7 16.1 20.8 33.0 34.0 Day 21 9.916.1 5.4 22.0 16.5 11.2 20.6 Day 28 6.4 10.2 4.8 8.3 8.4 18.6 9.1 *NDL:No Detectable levels of risperidone or 9-hydroxyrisperidone.

Tissue macroscopic evaluations showed minimal skin irritation in allgroups for 28 days. Implants were found to be firm and non-fragmentingwhen retrieved from rats at time points 1, 4, 7, 14, 21, and 28 dayspost dosing.

This implant retrieval study showed that all formulations releasedrisperidone 5.2% to 12.3% 24-hour post injection, and releasedrisperidone through day 14 (70-90%). Plasma risperidone results fromdays 21 and 28 were significantly less. Plasma levels of activerisperidone diminished to less than 10 ng/mL at day 28 which may beunacceptable.

In conclusion, risperidone/ATRIGEL® formulations prepared with 50/50PLGH (InV 0.36) polymers released risperidone more quickly than 65/35PLGH (InV 0.37). Formulations prepared with 65/35 PLGH (InV0.37)/N-methyl-2-pyrrolidone showed the most promising risperidonerelease over 28 days. Addition of 2% 70/30 PLG/PEG5000 (InV 0.79) inATRIGEL® reduced the initial burst.

Example 1.10

This 28-Day release kinetics and pharmacokinetics study was designed tofurther investigate the role of polymers in the risperidone releasecontrol. Six ATRIGEL®/Risperidone formulations containing 10%risperidone were examined in this study. The first three formulationswere focused on 65/35 PLGH (InV 0.37) based on the results of EXAMPLE1.9. The implant retrieval results were summarized in Table 15 and therelease profiles were depicted in FIG. 5. The mean active risperidoneplasma concentrations were provided in Table 16 and illustrated in FIG.6.

TABLE 15 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 10%Day 1 36.0 23.1 10.7 risperidone in 17.6 38% 65/35 PLGH 19.1 PLGH (InV32.3 0.37) + 10.3 2% PEG300/NMP Day 7 40.2 40.4 5.1 41.2 46.1 32.3 42.1Day 14 68.4 73.9 5.0 76.4 68.5 77.0 78.9 Day 21 89.7 90.1 3.5 92.0 95.087.1 86.6 Day 28 97.8 95.8 4.1 88.9 95.8 96.9 99.3 Group II: 10% Day 121.5 18.8 9.9 risperidone in 35.1 35% 65/35 PLGH 13.5 PLGH (InV 10.80.37) + 13.4 5% PEG300/NMP Day 7 45.4 42.4 11.5 54.4 38.1 49.2 24.7 Day14 68.7 77.7 5.2 79.6 80.7 81.2 78.4 Day 21 81.9 91.8 6.4 96.6 98.4 91.490.6 Day 28 99.0 97.3 2.2 97.8 94.1 96.0 99.5 Group III: 10% Day 1 25.822.6 6.5 Risperidone in 30.3 35% 65/35 PLGH (InV 24.1 0.37) + 19.6 5%70/30 PLG/PEG5000 13.2 (InV 0.79)/NMP Day 7 58.2 42.4 9.0 41.4 35.8 38.138.7 Day 14 71.8 70.3 4.0 68.5 76.1 65.4 69.6 Day 21 90.3 91.4 2.1 93.189.7 89.8 94.2 Day 28 92.8 93.6 2.5 91.1 91.6 96.5 96.1 Group IV: 10%Day 1 38.1 19.7 11.8 Risperidone in 22.7 40% 75/25 PLGH (InV 18.10.45)/NMP 12.2 7.4 Day 7 62.7 46.0 9.9 46.8 41.2 42.4 37.2 Day 14 67.357.7 10.4 65.3 62.8 47.7 45.2 Day 21 71.0 69.8 3.3 71.9 72.1 64.0 69.7Day 28 80.1 71.4 5.3 71.9 65.9 69.6 69.6 Group V: 10% Day 1 35.7 25.310.8 risperidone in 21.0 38% 75/25 PLGH (InV 32.1 0.45) + 29.0 2% 70/30PLG/ 8.5 PEG5000/NMP Day 7 51.4 42.8 13.9 44.7 59.3 34.2 24.2 Day 1466.0 52.4 8.4 47.6 54.7 48.9 44.9 Day 21 75.4 71.0 3.1 72.4 70.9 67.469.0 Day 28 74.7 74.1 6.3 84.6 71.4 70.9 68.8 Group VI: 10% Day 1 36.116.2 9.8 Risperidone in 28.0 40% 85/15 PLGH (InV 15.8 0.27)/NMP 16.635.4 Day 7 35.6 37.1 9.6 41.9 35.2 49.4 23.4 Day 14 NA 57.6 6.9 54.150.2 66.0 60.1 Day 21 86.3 75.7 6.8 73.3 77.1 67.6 74.2 Day 28 78.4 84.29.5 92.5 94.9 83.2 72.1

TABLE 16 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 10% Day 1 56.9 82.8 37.4 Risperidone in 53.238% 65/35 PLGH (InV 142.9 0.37) + 95.3 2% PEG 300/NMP 66.0 Day 7 29.248.2 19.4 41.5 80.7 47.5 41.9 Day 14 21.1 21.9 3.7 15.9 24.8 24.0 24.0Day 21 14.8 21.9 5.9 18.0 21.1 27.4 28.4 Day 28 3.9 3.0 2.1 — 4.2 4.1−0.1 Group II: 10% Day 1 75.4 79.4 17.4 Risperidone in 106.3 35% 65/35PLGH (InV 81.3 0.37) + 58.2 5% PEG 300/NMP 75.6 Day 7 64.9 92.2 25.078.4 93.1 131.7 92.7 Day 14 — 25.5 8.0 25.8 26.4 15.1 34.6 Day 21 21.122.3 4.4 16.9 24.2 27.2 — Day 28 4.2 1.4 1.8 −0.4 0.9 2.0 0.5 Group III:10% Day 1 37.7 50.8 9.9 Risperidone in 56.1 35% 65/35 PLGH (InV 52.20.37) + 63.3 5% 70/30 PLG/PEG5000 Day 7 31.1 79.1 38.4 (InV 0.79)/NMP53.3 101.8 128.2 81.0 Day 14 22.4 30.1 8.5 26.9 23.3 36.9 41.3 Day 2119.2 14.8 3.4 11.0 14.6 12.2 16.9 Day 28 −0.1 2.5 3.5 3.4 −1.5 7.4 3.0Group IV: 10% Day 1 96.4 96.4 7.7 Risperidone in 103.9 40% 75/25 PLGH(InV 91.8 0.45)/NMP 103.8 86.3 Day 7 36.6 45.8 9.6 37.4 58.5 43.5 52.8Day 14 12.1 17.8 6.1 20.3 13.0 16.3 27.1 Day 21 207.0 91.0 67.9 83.136.9 80.3 47.5 Day 28 2.3 6.5 4.1 10.1 11.4 5.0 3.5 Group V: 10% Day 174.4 81.8 7.0 Risperidone in 82.9 38% 75/25 PLGH (InV 86.1 0.45) + 75.02% 70/30PLG/PEG5000 90.5 (InV 0.79)/NMP Day 7 9.7 27.6 18.4 11.4 44.423.3 49.4 Day 14 12.8 35.0 20.9 19.5 61.1 52.2 29.2 Day 21 44.8 24.412.9 12.3 29.1 18.2 17.7 Day 28 −1.7 3.3 4.2 3.1 0.8 5.0 9.2 Group VI:10% Day 1 62.4 68.8 9.9 Risperidone in 87.8 40% 85/15 PLGH (InV 71.40.27)/NMP 66.2 77.1 Day 7 41.4 41.0 15.6 64.8 29.0 25.1 44.5 Day 14 —35.1 3.3 36.0 30.9 34.7 38.7 Day 21 34.2 38.5 9.4 36.8 26.2 45.1 50.2Day 28 0.7 7.2 4.5 5.0 12.7 8.3 9.2

Tissue macroscopic evaluations showed minimal skin irritation in allgroups for 28 days. Implants were found to be firm and non-fragmentingwhen retrieved from rats at 1, 4, 7, 14, 21, and 28 days post dosing.

The implant retrieval study showed the initial risperidone release ofall formulations ranged from 18-26% and released 50-75% of therisperidone dose at day 14. Risperidone release at day 28 ranged from71-98% of total dose. Plasma concentration of active risperidone at day1 ranged from 50-96 ng/ml and was less than 10 ng/mL at day 28 for allgroups.

The addition of PEG 300 or 5% 70/30 PLG/PEG5000 (InV 0.79) to the 65/35PLGH (InV 0.37) based ATRIGEL® delivery system increased the 24-hourburst of risperidone as compared with EXAMPLE 1.9, but had no affect onthe release rate after initial burst (Group I, II, and III). The 75/25PLGH (InV 0.45) and 85/15 PLGH (InV 0.27) polymers did not demonstrate a10% initial burst, but did afford a linear and slow risperidone release.

Example 1.11

The effects of risperidone loading were investigated in this 28-dayrelease kinetics and pharmacokinetics study using 65/35 PLGH (InV 0.37)and 50/50 poly(lactide-co-glycolide) (InV 0.33) polymers. The implantretrieval results were summarized in Table 17 and the release profileswere shown in FIG. 7. The mean active risperidone plasma concentrationswere presented in Table 18 and illustrated in FIG. 8.

TABLE 17 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 10%Day 1 26.4 15.0 10.9 Risperidone in 22.1 40% 65/35 PLGH (InV 16.50.37)/60% NMP 11.9 −1.8 Day 7 50.2 39.6 6.3 35.3 34.4 37.9 40.2 Day 1462.9 64.0 5.7 62.8 55.7 69.8 69.0 Day 21 78.9 84.3 3.2 85.5 83.8 87.186.1 Day 28 94.5 93.0 1.3 91.2 93.2 94.0 92.2 Group II: 20% Day 1 9.89.5 3.0 Risperidone in 14.3 40% 65/35 PLGH (InV 9.3 0.37)/60% NMP 7.46.7 Day 7 52.9 39.8 9.6 42.9 28.6 42.1 32.4 Day 14 62.8 66.7 3.3 70.866.9 68.9 64.2 Day 21 80.8 74.9 8.0 82.7 67.4 65.2 78.5 Day 28 96.6 89.85.0 91.3 90.3 88.2 82.8 Group III: 25% Day 1 10.3 13.4 3.7 Risperidonein 15.9 40% 65/35 PLGH (InV 9.6 0.37)/60% NMP 18.2 13.1 Day 7 49.5 40.110.3 47.1 40.1 40.7 23.2 Day 14 60.8 60.4 7.7 47.3 63.6 67.6 62.8 Day 2198.5 80.3 16.4 97.7 69.4 70.8 65.1 Day 28 78.7 80.1 11.6 93.1 87.8 62.678.3 Group IV: 20% Day 1 17.2 14.0 10.9 Risperidone in 1.8 40% 50/50 PLG(InV 30.8 0.33)/60% NMP 12.2 8.2 Day 7 37.1 43.2 9.0 40.5 59.1 39.6 39.9Day 14 72.6 76.9 8.5 73.5 68.8 90.5 79.3 Day 21 91.4 95.1 3.2 95.8 97.698.6 92.3 Day 28 99.4 99.7 0.3 99.9 99.4 99.9 99.7 Group V: 25% Day 113.4 11.7 4.1 Risperidone in 9.6 40% 50/50 PLG (InV 18.1 0.33)/60% NMP8.1 9.2 Day 7 41.8 46.7 6.9 46.0 38.5 54.2 53.1 Day 14 79.6 78.1 10.689.6 64.9 69.8 86.4 Day 21 88.4 86.1 4.7 85.8 91.4 78.7 86.2 Day 28 98.598.9 1.1 98.3 100.0 100.0 97.6

TABLE 18 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 10% Day 1 59.1 39.2 13.0 Risperidone in 22.840% 65/35 PLGH (InV 40.3 0.37)/60% NMP 35.9 38.0 Day 7 30.5 37.8 16.867.3 27.5 28.5 35.0 Day 14 13.0 20.7 8.1 17.4 34.0 17.0 22.0 Day 21 18.615.3 2.6 16.0 15.8 14.5 11.4 Day 28 12.4 13.8 3.8 13.3 18.5 8.5 16.3Group II: 20% Day 1 97.1 65.7 27.4 Risperidone in 37.3 40% 65/35 PLGH(InV 48.1 0.37)/NMP/60% NMP 53.1 92.9 Day 7 61.0 56.9 15.8 36.3 45.167.1 74.8 Day 14 64.7 43.3 14.5 24.5 38.5 44.6 44.1 Day 21 16.6 35.327.0 24.7 82.5 20.8 31.9 Day 28 16.2 32.3 20.0 16.6 24.3 63.2 41.0 GroupIII: 25% Day 1 98.6 110.5 43.5 Risperidone in 125.8 40% 65/35 PLGH (InV47.9 0.37)/NMP 112.3 167.8 Day 7 104.0 92.1 40.5 49.9 63.5 89.2 153.8Day 14 26.1 46.5 29.5 34.1 98.4 33.4 40.3 Day 21 9.9 28.2 15.6 17.1 26.346.9 40.7 Day 28 72.6 54.0 21.7 27.5 34.5 61.8 73.7 Group IV: 20% Day 1115.2 90.6 24.4 Risperidone in 115.2 40% 50/50 PLG (InV 86.2 0.33)/NMP59.7 76.5 Day 7 89.2 81.5 15.8 69.3 105.8 70.8 72.5 Day 14 25.2 30.8 9.818.6 39.2 28.7 42.1 Day 21 45.5 27.5 14.5 32.2 26.4 5.3 28.3 Day 28 17.513.8 6.8 13.8 5.8 9.1 23.0 Group V: 25% Day 1 246.5 227.5 27.3Risperidone in 215.6 40% 50/50 PLG (InV 197.0 0.33)/NMP/60% NMP 213.8264.5 Day 7 102.4 124.4 30.3 84.2 144.2 134.0 157.4 Day 14 48.6 55.212.1 58.5 70.4 38.5 60.2 Day 21 71.2 36.1 19.9 21.7 29.6 29.6 28.3 Day28 19.1 25.2 19.1 25.2 16.5 7.8 57.5

Tissue macroscopic evaluations showed minimal skin irritation in allgroups. Implants were found to be firm and non-fragmenting whenretrieved from rats at time points of 1, 4, 7, 14, 21, and 28 days postdosing.

The test articles in this study showed a 9.5±3.0% (Group II) to15.0±10.9% (Group I) release of risperidone 24 hours post injection andrisperidone release ranged from 80.1±11.6% to 99.7±0.3% at day 28 asindicated by the implant retrieval study. Group II, 20% risperidonesuspended in 40% 65/35 PLGH (InV 0.37)/60% N-methyl-2-pyrrolidonedemonstrated the best release of risperidone over 28 days. The maximumactive risperidone plasma concentrations (C_(max)) were reached 24 hourspost injection for all groups. The active risperidone plasmaconcentrations decreased and remained at higher than 13.8 ng/ml over 28days.

In conclusion, formulations containing 10% to 25% risperidone in adelivery system prepared with 40% 65/35 PLGH (InV 0.37) and 60%N-methyl-2-pyrrolidone gave low initial 24-hour burst and sustainedrisperidone release for 28 days. The 20% load formulation appeared toshow the best-controlled risperidone release for 28 days. The ATRIGEL®delivery system based on 65/35 PLGH (InV 0.37) demonstrated bettercontrol on the risperidone release compared to 50/50poly(lactide-co-glycolide) (InV 0.33) over 28 days. There was acorrelation between the rat plasma active risperidone concentrationsimplant risperidone release data. The slower the release rate decline,the higher the active risperidone plasma concentration at Day 14 to 28.The AUC_(Day 0-28) was proportional to risperidone dosage.

Example 1.14

Four ATRIGEL®/Risperidone formulations containing 20% risperidone wereevaluated in this release kinetics and pharmacokinetics study. The bestformulation (Group II) in EXAMPLE 1.11 was further investigated by usingpurified 65/35 PLGH (InV 0.37). The effect of blending 15% 50/50 PLGH(InV 0.36) into slow release polymer 85/15 PLGH (InV 0.27) or 75/25 PLGH(InV 0.45) was also investigated. The implant retrieval results weresummarized in Table 19 and the release profiles were depicted in FIG. 9.The mean active risperidone plasma concentrations were provided in Table20 and illustrated in FIG. 10.

TABLE 19 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 20%Day 1 26.7 15.0 7.5 Risperidone in 17.4 25% 85/15 PLGH 10.5 (InV 0.27) +13.4 15% 50/50 PLGH (InV 7.1 0.36)/60% NMP Day 7 42.7 37.7 4.6 35.6 39.639.8 30.7 Day 14 55.1 55.8 7.0 64.5 50.0 48.2 61.3 Day 21 81.6 83.5 9.385.1 73.4 98.2 79.2 Day 28 85.3 76.6 13.1 62.8 66.0 75.0 94.0 Group II:20% Day 1 25.4 18.4 4.8 Risperidone in 18.8 25% 75/25 PLGH 17.3 (InV0.45) + 18.8 15% 50/50 PLGH (InV 11.8 0.36)/60% NMP Day 7 54.0 46.4 5.345.0 44.6 39.7 48.6 Day 14 67.0 63.0 6.0 60.7 66.9 66.9 53.3 Day 21 66.671.2 4.6 72.3 78.0 67.2 71.8 Day 28 84.0 80.3 8.7 76.4 75.1 72.3 93.8Group III: 20% Day 1 30.2 24.3 8.1 Risperidone in 15.2 40% 50/50 PLG(InV 27.3 0.24)/60% NMP 16.0 32.7 Day 7 34.4 29.8 4.3 26.1 24.6 30.433.4 Day 14 70.3 68.3 6.1 60.5 74.3 73.2 63.4 Day 21 87.7 80.0 9.8 66.388.1 73.1 84.9 Day 28 100.1 86.6 9.9 73.3 90.6 82.6 86.6 Group IV: 20%Day 1 32.3 19.2 7.9 Risperidone in 15.0 40% 65/35 PLGH (InV 20.9 0.37)purified/60% 14.2 NMP 13.7 Day 7 44.7 43.9 0.6 43.7 43.7 43.2 44.3 Day14 80.4 68.7 11.1 78.2 62.7 68.7 53.5 Day 21 78.4 75.1 5.7 81.1 71.977.5 66.8 Day 28 98.8 93.6 8.9 99.8 79.5 100.0 90.0

TABLE 20 28-Day Active Risperidone Plasma Concentrations Test Time %Mean % Standard Article Point Released Released Deviation Group I: 20%Day 1 117.9 119.1 66.6 Risperidone in 95.1 25% 85/15 PLGH (InV 58.70.27) + 232.2 15% 50/50 PLGH (InV 91.7 0.36)/NMP Day 7 59.4 44.2 15.360.7 28.6 41.6 30.5 Day 14 98.9 75.0 24.1 85.7 81.9 73.3 35.2 Day 2158.5 29.3 20.0 41.0 20.6 14.8 11.4 Day 28 44.1 26.4 11.1 18.1 17.6 30.022.3 Group II: 20% Day 1 105.1 79.1 33.8 Risperidone in 51.5 25% 75/25PLGH (InV 116.1 0.45) + 37.5 15% 50/50 PLGH (InV 85.4 0.36)/NMP Day 722.1 38.3 20.8 28.6 74.4 36.8 29.8 Day 14 58.2 40.6 12.7 49.9 29.2 31.234.5 Day 21 52.8 29.8 17.0 39.6 15.7 29.4 11.6 Day 28 24.8 28.0 13.9Lost sample 15.2 47.7 24.3 Group III: 20% Day 1 75.2 71.2 16.5Risperidone in 52.6 40% 50/50 PLG (InV 94.5 0.24)/NMP 75.5 58.1 Day 734.0 51.0 25.0 29.0 70.2 85.0 36.9 Day 14 35.7 55.8 28.6 68.8 18.1 66.589.9 Day 21 33.3 28.2 11.0 34.6 38.9 22.4 11.9 Day 28 22.8 16.5 7.8 19.318.8 18.6 2.9 Group IV: 20% Day 1 76.6 67.6 11.1 Risperidone in 40% 55.565/35 PLGH (InV 0.37) 67.7 purified/NMP 57.5 80.5 Day 7 104.8 55.1 39.019.7 89.4 31.5 30.3 Day 14 133.6 72.1 46.2 109.2 33.1 36.6 47.8 Day 2120.8 31.8 18.9 13.6 50.8 53.6 20.1 Day 28 20.4 27.0 4.5 30.3 Lost sample28.2 29.0

Tissue macroscopic evaluations showed minimal skin irritation in allgroups. Retrieved implants were found to be firm and non-fragmentingwhen retrieved from rats at 1, 4, 7, 14, 21, and 28 days post dosing.

The test articles in this study showed a 15.0±7.5% (Group I) to24.3±8.1% (Group III) risperidone release at 24 hours post injection and76.6±13.1% to 93.6±8.9% release at day 28 as indicated by the implantretrieval study. The maximum active risperidone plasma concentrations(C_(max)) were reached 24 hours post injection for all groups and rangedfrom 67-119 ng/ml. The active risperidone plasma concentrationsdecreased and remained at higher than 16.5 ng/ml over 28 days.

In conclusion, all Test Articles provided sustained release ofrisperidone over 28 days, and showed 16.5 ng/ml or higher activerisperidone plasma concentrations in the course of the study.Purification of 65/35 PLGH (InV 0.37) increased the initial release ofrisperidone, but did not affect the release after Day 1 as compared withEXAMPLE 1.11. Blending 50/50 PLGH (InV 0.36) into 85/15 PLGH (InV 0.27)showed promising risperidone release from day 1 to day 28.

Example 1.15

A 28-day release study was conducted focusing on two selected ATRIGEL®delivery systems with 15% and 20% risperidone loading. The two selectedsystems were: (1) 45% 65/35 PLGH (InV 0.37)/55% N-methyl-2-pyrrolidoneand (2) 25% 85/15 PLGH (InV 0.27)+20% 50/50 PLGH (InV 0.36)/55%N-methyl-2-pyrrolidone. The increased polymer loading was formulated todecrease the initial risperidone release. The implant retrieval resultswere summarized in Table 21 and the release profiles were depicted inFIG. 11. The mean active risperidone plasma concentrations werepresented in Table 22 and illustrated in FIG. 12.

TABLE 21 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 20%Day 1 41.4 22.4 13.9 Risperidone in 29.0 45% 65/35 PLGH (InV 21.30.37)/NMP 16.0 4.5 Day 7 42.6 43.7 4.9 48.7 48.7 37.9 40.4 Day 14 65.469.1 9.2 68.2 84.5 67.7 59.9 Day 21 77.7 80.2 3.1 81.6 76.8 80.5 84.4Day 28 90.6 91.6 2.5 88.2 91.3 94.8 93.1 Group II: 15% Day 1 19.2 14.66.2 Risperidone in 12.1 45% 65/35 PLGH (InV 21.5 0.37)/NMP 14.2 5.9 Day7 34.5 32.8 2.6 33.6 31.3 29.2 35.6 Day 14 69.8 61.7 6.2 64.9 62.8 55.955.0 Day 21 85.1 82.8 3.5 80.1 87.7 79.4 81.8 Day 28 93.3 93.2 2.2 94.393.1 89.7 95.5 Group III: 20% Day 1 12.2 18.7 5.7 Risperidone in 17.725% 85/15 PLGH (InV 24.5 0.27) + 24.7 20% 50/50 PLGH (InV 14.3 0.36)/55%NMP Day 7 42.7 40.1 6.7 49.9 40.0 32.4 35.7 Day 14 60.5 57.5 2.1 lost56.5 55.8 57.2 Day 21 59.7 74.2 12.6 77.9 64.1 91.4 77.8 Day 28 86.293.7 5.6 98.7 89.9 95.0 98.9 Group IV: 15% Day 1 11.5 12.3 4.0Risperidone in 10.9 25% 85/15 PLGH (InV 17.6 0.27) + 14.5 20% 50/50 PLGH(InV 7.0 0.36)/55% NMP Day 7 42.0 43.6 3.7 43.2 39.9 43.2 49.7 Day 1465.2 64.8 6.6 63.4 65.5 55.6 74.0 Day 21 88.4 84.2 4.7 79.0 79.4 87.986.6 Day 28 89.4 91.5 4.0 98.5 88.7 90.9 90.2

TABLE 22 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 20% Day 1 130.0 138.1 30.4 Risperidone in 95.045% 65/35 PLGH (InV 132.3 0.37)/NMP 159.3 173.9 Day 7 56.8 118.2 66.9 *208.1 79.8 128.0 Day 14 32.5 108.6 52.9 172.2 95.1 100.9 142.2 Day 2139.7 48.4 31.8 21.8 * * 83.6 Day 28 36.0 43.7 13.1 32.8 65.8 39.2 44.7Group II: 15% Day 1 126.2 111.6 42.3 Risperidone in 130.3 45% 65/35 PLGH(InV 70.7 0.37)/NMP 66.0 165.1 Day 7 * 71.5 26.1 40.7 94.5 91.7 59.0 Day14 90.6 67.8 21.9 52.4 80.4 78.0 37.8 Day 21 30.1 28.6 10.8 39.6 17.417.7 38.3 Day 28 17.4 21.0 5.9 20.8 13.3 27.3 26.0 Group III: 20% Day 1113.7 160.4 31.7 Risperidone in 174.4 25% 85/15 PLGH (InV 169.5 0.27) +183.9 20% 50/50 PLGH (InV * 0.36)/55% NMP Day 7 39.7 69.1 25.8 109.071.1 54.7 70.8 Day 14 122.0 92.7 22.4 111.2 77.3 71.3 81.8 Day 21 46.641.0 6.7 * 46.6 37.2 33.5 Day 28 60.8 33.1 15.9 25.1 25.2 22.5 31.7Group IV: 15% Day 1 100.5 95.1 18.6 Risperidone in 104.6 25% 85/15 PLGH(InV * 0.27) + 107.9 20% 50/50 PLGH (InV 67.6 0.36)/55% NMP Day 7 65.770.9 7.7 81.0 lost sample 64.4 72.7 Day 14 79.6 70.4 26.0 80.4 24.2 80.387.7 Day 21 23.9 45.7 21.5 79.9 31.9 46.8 45.8 Day 28 26.0 25.1 19.9 0.055.7 23.9 20.1

The test articles in this study showed a 12.3±4.0% (Group IV) to17.7±6.9% (Group I) risperidone release at 24 hours post injection and a91.5±4.0% to 93.7±5.6% release at day 28 as indicated by the implantretrieval study. All Test Articles showed linear release of risperidoneover 28 days. The maximum active risperidone plasma concentrations(C_(max)) were reached 24 hours post injection for all groups and rangedfrom 95.1 to 160.4 ng/ml. The active risperidone plasma concentrationsdecreased and remained greater than 13.8 ng/ml over 28 days.

In conclusion, formulations based on 45% 65/35 PLGH (InV 0.37) and 55%N-methyl-2-pyrrolidone, using a lower risperidone load (15%) formulationappeared to show better overall release of drug than 20% risperidoneload. Formulations using a 25% 85/15 PLGH (InV 0.27) plus 20% 50/50 PLGH(InV 0.36) and 55% N-methyl-2-pyrrolidone, with a 15% risperidone loadappeared to control risperidone release better than 20%. No majorrisperidone release differences were obtained between these two ATRIGEL®formulations. The area under the curve (AUC_(Day 0-28)) of all fourformulations was proportional to risperidone dosage.

Example 1.12

Eight Test Articles with 15% risperidone loading were evaluated in this14-Day release kinetics and pharmacokinetics study. The affect of 38% to45% polymer (65/35 PLGH (InV 0.37) concentration on the risperidonerelease was evaluated. The implant retrieval results were summarized inTable 23 and the mean active risperidone plasma concentrations wereprovided in Table 24.

TABLE 23 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 15%Day 1 21.9 20.7 6.9 Risperidone in 14.5 38% 65/35 PLGH (InV 24.70.37)/62% NMP 13.0 29.2 Day 14 72.8 73.1 5.9 74.9 67.8 82.2 68.1 GroupII: 15% Day 1 22.3 17.4 5.0 Risperidone in 18.5 40% 65/35 PLGH (InV 21.80.37)/60% NMP 12.9 11.5 Day 14 76.2 77.2 8.2 85.0 80.8 80.2 63.7 GroupIII: 15% Day 1 18.0 14.3 2.8 Risperidone in 10.9 42.5% 65/35 PLGH (InV12.1 0.37)/57.5% NMP 15.4 15.2 Day 14 76.0 73.8 4.3 76.5 72.0 77.3 67.1Group IV: 15% Day 1 11.3 13.3 5.3 Risperidone in 20.9 45% 65/35 PLGH(InV 16.5 0.37)/55% NMP 10.2 7.7 Day 14 62.3 66.9 3.2 69.5 67.8 65.169.8 Group V: 15% Day 1 36.1 22.0 10.7 Risperidone in 25.8 45% 75/25PLGH (InV 8.5 0.24)/55% NMP 14.8 24.9 Day 14 78.9 80.6 8.9 75.4 87.269.7 91.8 Group VI: 15% Day 1 18.4 14.4 9.8 Risperidone in 10.2 20%85/15 PLGH (InV 6.3 0.27) + 7.4 20% 50/50 PLGH (InV 29.7 0.36)/60% NMPDay 14 86.1 75.6 9.7 59.6 76.3 78.4 77.7 Group VII: 15% Day 1 8.2 11.46.6 Risperidone in 11.9 40% 65/35 PLGH (InV 9.7 0.37) + 22.3 5%PEG8000-PLG (InV 5.0 0.27)/55% NMP Day 14 66.8 73.3 7.4 76.5 67.6 84.770.7 Group VIII: 15% Day 1 11.4 10.8 2.9 Risperidone in 9.1 22.2% 85/15PLGH (InV 11.4 0.27) + 15.0 17.8% 65/35 PLGH (InV 7.2 0.37)/60% NMP Day14 66.0 68.7 4.8 63.7 69.0 68.6 76.4

TABLE 24 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 15% Day 1 111.4 78.7 23.4 Risperidone in 56.838% 65/35 PLGH (InV 94.5 0.37)/62% NMP 60.9 69.8 Day 14 43.3 22.0 22.72.9 2.9 49.6 11.6 Group II: 15% Day 1 48.2 69.3 26.6 Risperidone in 53.640% 65/35 PLGH (InV 64.6 0.37)/60% NMP 64.9 115.0 Day 14 22.0 42.9 15.844.9 66.4 39.5 41.7 Group III: 15% Day 1 69.1 62.4 15.6 Risperidone in46.6 42.5% 65/35 PLGH (InV 46.5 0.37)/57.5% NMP 82.7 67.0 Day 14 13.851.6 29.7 73.6 36.7 88.5 45.6 Group IV: 15% Day 1 48.5 53.5 3.6Risperidone in 51.0 45% 65/35 PLGH (InV 55.2 0.37)/55% NMP 57.2 55.6 Day14 30.5 41.5 11.6 34.6 48.4 58.5 35.8 Group VI: 15% Day 1 69.4 81.4 22.9Risperidone in 105.2 20% 85/15 PLGH 107.2 (InV 0.27) + 60.7 20% 50/50PLGH (InV 64.4 0.36)/60% NMP Day 14 32.8 35.4 9.8 48.6 30.1 23.6 41.8Group VII: 15% Day 1 48.9 69.2 25.5 Risperidone in 60.1 40% 65/35 PLGH106.2 (InV 0.37) + 84.1 5% PEG8000-PLG (InV 46.6 0.27)/55% NMP Day 1429.8 54.8 20.4 78.3 43.4 49.6 72.9 Group VIII: 15% Day 1 45.0 56.7 21.1Risperidone in 53.7 22.2% 85/15 PLGH 88.4 (InV 0.27) + 63.6 17.8% 65/35PLGH (InV 32.6 0.37)/60% NMP Day 14 45.1 47.4 18.5 76.0 29.1 33.9 52.9

The macroscopic evaluation showed that the tissue reaction were mostlyunremarkable throughout the study. All implants were firm andnon-fragmenting at day 1 and 14. One implant from Group VIII, day 14,was slightly mottled in coloration.

The implant retrieval data showed that the eight test articles released10.8±2.9% (Group VIII) to 22.0±10.7% (Group V) risperidone at 24 hourspost injection and 66.9±3.2% (Group IV) to 80.6±8.9% (Group V) at 14days post injection. Group IV displayed the best release rate ofrisperidone in this study with 13.3±5.3% release at Day 1 and 66.9±3.2%release at day 14. The test article used for Group IV was 15%risperidone suspended in a delivery system prepared with 45% 65/35 PLGH(InV 0.37) and 55% N-methyl-2-pyrrolidone. The active risperidone plasmaconcentrations of all groups except Group V were analyzed. The activerisperidone plasma concentrations ranged from 53.5±3.6 (Group IV) to81.4±22.9 ng/ml (Group V) at 24 hours post injection and 22.0±22.7(Group I) to 54.8±20.4 ng/ml (Group VII) at 14 days post injection.

In conclusion, the concentration of the polymer in ATRIGEL® deliverysystem appears to be a factor in controlling the release of risperidone.The 24-hour initial release of risperidone decreased with the increaseof the polymer concentration. A correlation was obtained between the ratplasma concentrations of active risperidone and implant release data.The higher the 24-hour release of risperidone, the higher the activerisperidone concentration in plasma.

Example 1.13

The final 28-Day release and pharmacokinetic study was conducted toconfirm the findings in previous studies. In addition, the bestcombination of risperidone and polymer loading were evaluated. None orminimal skin irritation was confirmed again in this study. All implantswere firm and non-fragmenting from day 1 to day 28.

Overall, all formulations showed similar linear sustained release ofrisperidone during the 28-day study. The implant retrieval study showed10.5% (Groups II and V) to 17.3±7.0% (Group I) risperidone release ofall the Test Articles at 24 hours post injection and a 86.3±4.1% (GroupV) to 98.6±1.0% (Group IV) release at day 28. The maximum activerisperidone plasma concentrations (C_(max)) were reached 24 hours postinjection for all groups and ranged from 62.1 (Group III) to 168.9 ng/ml(Group II). The active risperidone plasma concentrations decreased andremained at greater than 15.8 ng/ml (Group IV) over 28 days for allgroups. Groups II and V showed the best release profile up to day 21,but showed very slow risperidone release between day 21 to day 28. Onthe other hand, the plasma concentrations of these groups at day 21 andday 28 were greater than 30 ng/ml, which was inconsistent with theimplant release data. The data from this study compared to the previousrelease and pharmacokinetic data in EXAMPLES 1.11, 1.14, and 1.15,demonstrated that the risperidone release from this formulation wasstill remarkable, and the pharmacokinetic data were reliable. Theimplant retrieval results were summarized in Table 25 and the releaseprofiles were depicted in FIG. 13. The mean active plasma risperidoneconcentrations were presented in Table 26 and illustrated in FIG. 14.

TABLE 25 28-Day Risperidone Release From ATRIGEL ® Implants Test Time %Mean % Standard Article Point Released Released Deviation Group I: 15%Day 1 28.9 17.3 7.0 Risperidone in 16.6 40% 65/35 PLGH (InV 17.30.37)/60% NMP 12.3 11.3 Day 7 10.2 33.3 13.4 40.1 44.2 36.2 35.7 Day 1452.3 64.9 9.3 76.2 69.9 66.7 59.2 Day 21 84.4 82.1 5.1 79.0 79.7 77.389.9 Day 28 93.4 94.6 3.9 99.7 97.6 91.2 91.0 Group II: 20% Day 1 18.510.5 4.9 Risperidone in 7.0 40% 65/35 PLGH (InV 10.7 0.37)/60% NMP 10.16.2 Day 7 35.5 33.8 2.1 33.7 32.4 36.3 31.2 Day 14 66.9 66.5 4.0 67.359.9 70.8 67.7 Day 21 74.9 87.7 9.1 83.8 87.3 96.7 96.0 Day 28 85.3 88.93.9 91.1 90.6 93.2 84.2 Group III: 15% Day 1 26.6 16.7 13.5 Risperidonein 21.2 45% 65/35 PLGH (InV 29.4 0.37)/60% NMP 9.7 −3.2 Day 7 39.5 36.54.5 39.5 40.3 31.6 31.5 Day 14 68.4 68.2 5.9 70.0 76.2 66.7 59.8 Day 2184.2 84.9 6.5 88.7 88.9 73.9 89.0 Day 28 95.6 93.7 2.0 96.0 92.0 93.091.8 Group IV: 20% Day 1 32.8 13.6 16.1 Risperidone in 26.1 45% 65/35PLGH (InV 12.6 0.37)/60% NMP 3.3 −6.7 Day 7 49.7 39.6 9.0 38.0 47.3 27.635.7 Day 14 66.2 68.4 10.8 78.7 80.3 56.4 60.2 Day 21 92.6 91.4 4.5 97.393.1 85.6 88.5 Day 28 98.9 98.6 1.0 98.7 96.8 99.0 99.5 Group V: 20% Day1 12.2 10.5 1.3 Risperidone in 9.5 20% 85/15 PLGH 9.2 (InV 0.27) + 10.020% 50/50 PLGH (InV 11.6 0.36)/60% NMP Day 7 35.6 40.2 4.4 36.7 46.143.2 39.5 Day 14 59.7 60.7 6.1 64.4 52.1 59.0 68.4 Day 21 79.5 81.3 10.674.6 81.9 98.9 71.6 Day 28 91.9 86.3 4.1 80.5 85.7 88.0 85.4

TABLE 26 28-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 15% Day 1 66.1 83.2 26.4 Risperidone in 67.740% 65/35 PLGH (InV 127.9 0.37)/60% NMP 67.6 86.8 Day 7 43.7 83.7 30.966.5 108.4 80.3 119.8 Day 14 47.2 36.5 6.7 33.7 29.9 33.4 38.5 Day 2120.9 32.0 7.6 39.1 28.8 32.3 38.7 Day 28 58.1 31.2 23.4 8.0 12.7 23.153.9 Group II: 20% Day 1 271.4 168.9 75.2 Risperidone in 124.7 40% 65/35PLGH (InV 152.5 0.37)/60% NMP 80.9 215.0 Day 7 24.7 51.9 28.1 63.6 18.974.0 78.5 Day 14 42.0 60.3 38.0 37.1 45.9 127.8 48.9 Day 21 38.8 43.723.6 22.2 39.3 84.0 34.1 Day 28 39.1 38.5 8.9 29.9 51.2 30.4 41.8 GroupIII: 15% Day 1 50.2 62.1 23.6 Risperidone in 38.9 45% 65/35 PLGH (InV98.7 0.37)/60% NMP 71.6 51.1 Day 7 68.7 62.4 16.7 80.3 71.4 53.8 37.9Day 14 39.2 43.1 8.0 52.0 39.5 33.9 51.1 Day 21 41.9 33.3 8.7 28.1 26.826.1 43.5 Day 28 19.7 22.7 14.0 47.3 13.2 16.6 16.6 Group IV: 20% Day 1116.8 100.6 17.3 Risperidone in 90.8 45% 65/35 PLGH (InV 112.0 0.37)/55%NMP 108.4 75.2 Day 7 64.9 66.2 16.5 43.3 73.0 88.4 61.5 Day 14 51.6 59.115.5 50.5 86.5 56.1 51.0 Day 21 21.6 36.5 15.7 19.5 42.3 42.9 56.5 Day28 17.8 15.8 5.5 12.5 22.3 18.0 8.3 Group V: 20% Day 1 84.0 100.7 28.6Risperidone in 77.0 20% 85/15 PLGH 139.0 (InV 0.27) + 123.7 20% 50/50PLGH 79.7 (InV 0.36)/60% NMP Day 7 72.4 62.4 22.0 89.8 46.4 34.4 69.0Day 14 32.6 41.2 6.5 41.6 43.1 50.3 38.4 Day 21 69.0 43.7 22.6 9.9 36.645.1 57.9 Day 28 24.1 50.2 19.8 41.3 51.8 78.1 55.8

In conclusion, 15% risperidone dose formulations gave lower 24-hourinitial burst. Polymer loading of 40% or 45% appeared to have minimaleffect on the overall release of risperidone, but did have a largeimpact on the syringeability of the reconstituted formulations. However,the higher the drug and polymer load, the more difficult the injection.The higher the drug loading, the smaller the injection volume. A 15%risperidone loading in the total formulation and 45% polymer loadings inthe ATRIGEL® delivery system appears to be a better formulation choice.The pharmacokinetic data in this study generally supported the implantretrieval results.

Example 2 Pharmacokinetics Studies in Rabbits

The purpose of this study was to determine and compare thepharmacokinetic profiles of risperidone/ATRIGEL® formulation andRISPERDAL® CONSTA® formulations. The previous risperidone/ATRIGEL®formulation studies evaluated in rats resulted in selecting a 15%risperidone suspended in 45% 65/35 PLGHp (37 kDa)/N-methyl-2-pyrrolidoneformulation for further development. The selected formulation wasevaluated in two rabbit preclinical studies conducted in New ZealandWhite rabbits. The two studies were EXAMPLES 2.1 and 2.2. Five or tenrabbits per Test Article were injected subcutaneously with a full doseof the test article containing 30, 60, or 120 mg risperidone.

At selected time points, five or ten rabbits per Test Article were bled(about 3 mL) via marginal ear vein. Blood was collected in labeledpotassium EDTA tubes. The blood was centrifuged for 10 min at 3000 rpm.The plasma fraction was transferred to labeled 5 mL plastic culturetubes and stored at −86° C. The plasma was extracted following thePlasma SPE Extraction Procedure For Active Risperidone Plasma Analysis,described above. The active risperidone concentrations were analyzedusing the Plasma SPE Extraction Procedure For Active Risperidone PlasmaAnalysis, described above. The active risperidone plasma concentrationwas calculated based on both risperidone and 9-hydroxyrisperidone.

On the last day of the study, the rabbits were anesthetized, bled viacardiac puncture and promptly euthanized. The test sites wereimmediately dissected and evaluated for macroscopic tissue reactions.Implants were removed and physically debrided of tissue, andprecipitation characteristics documented. Representative photographswere taken of the test sites.

Personnel evaluated injection sites at each time point for anyabnormalities including redness, bleeding, swelling, discharge,bruising, and test article extrusion. Additionally, personnel observedanimals post administration for signs of overt toxicity for the durationof the study.

The two studies indicated that (1) all doses of the Risperidone/ATRIGEL®formulation showed an initial burst of risperidone within the first 8hours post dosing and the second maximum plasma concentration (C_(max))of active risperidone was reached at day 7 to 9 for 60 and 120 mg doseformulations, (2) the area under the curve (AUC) was dose proportionalfor all three doses, (3) the active risperidone plasma concentrationexceeded 25 ng/mL through Day 35 in all three doses and the plasmalevels fell below 25 ng/mL at Day 42 and were near 0 at day 50, (4) atone hour post injection, the 50 mg RISPERDAL® CONSTA® showed plasmaconcentrations greater than 25 ng/mL, the plasma risperidoneconcentrations decreased to near zero until Day 22 when the plasmarisperidone concentration exceeded 100 ng/mL, plasma risperidoneconcentrations decreased to 12 ng/mL at Day 35 and decreased to nearzero at days 42 through 50, (5) the AUC_(Day 0-50) of 30 mgRisperidone/ATRIGEL® was comparable to 50 mg RISPERDAL® CONSTA®, and (6)the Pharmacokinetic profiles of all three doses were repeatable.

Example 2.3

A pharmacokinetics study in rabbits was conducted to evaluate theprevious data obtained from the 28-day rat studies. TheRisperidone/ATRIGEL® formulation chosen from the rat studies was 15%risperidone suspended in 45% 65/35 PLGH (37 kDa) and 55%N-methyl-2-pyrrolidone. The subcutaneous doses in the rabbit were 30,60, and 120 mg risperidone from this formulation. The injection volumesinto the rabbit were 0.2, 0.4, and 0.8 mL. A positive control of 50 mgRISPERDAL® CONSTA® (2 mL IM injection) was also used in this study. Thestudy duration was 50 days with blood collection at 1, 2, 6, 12 hours,and 1, 3, 7, 14, 22, 28, 35, 42, and 45 days via marginal ear vein. Atday 50, after blood collection by cardiac puncture the animal waseuthanized and the implant was removed for determination of risperidoneremaining in the implant. The plasma was extracted following the PlasmaSPE Extraction Procedure For Active Risperidone Plasma Analysis,described above. The active risperidone concentrations were analyzedusing the Reversed Phase High Performance Liquid Chromatography MethodFor The Quantization of Risperidone And 9-Hydroxyrisperidone, describedabove. The active risperidone concentrations at each time point werelisted in Table 27.

TABLE 27 50-Day Active Risperidone Plasma Concentrations Plasma MeanConcen- Concen- Test Time tration tration Standard Article Point ng/mlng/ml Deviation Group I: 50 mg Day 0.04 39.5 35.7 11.5 RISPERDAL ® 49.7CONSTA ® 23.5 41.6 24.0 Day 0.08 22.6 24.2 7.0 34.2 17.7 28.2 18.2 Day0.25 9.2 9.6 2.9 14.4 8.5 9.2 6.8 Day 0.5 0.2 3.0 2.0 4.9 2.5 4.9 2.3Day 1 0.2 2.7 1.5 3.2 3.5 3.8 2.9 Day 3 14.3 8.3 3.6 8.2 5.8 8.2 5.0 Day7 3.5 4.3 1.6 4.7 5.8 5.6 2.0 Day 14 0.2 5.1 3.5 8.4 8.4 3.5 5.1 Day 2277.3 102.5 25.7 136.5 101.1 119.1 78.6 Day 28 27.8 58.1 25.7 63.8 94.464.8 39.8 Day 35 11.9 15.8 3.8 14.8 21.9 13.9 16.6 Day 42 32.5 108.652.9 172.2 95.1 100.9 142.2 Day 45 10.3 2.1 4.6 0.0 0.0 0.0 0.0 Day 4510.3 2.1 4.6 0.0 0.0 0.0 0.0 Day 50 0.0 1.7 3.8 0.0 0.0 0.0 8.4 GroupII: 120 mg Day 0.04 98.8 103.5 23.4 Risperidone 79.3 (15% Risperidone137.3 in 45% 115.7 65/35PLGHp(InV 86.7 0.37) and 55% NMP) Day 0.08 134.2166.6 35.7 184.2 220.5 152.4 141.6 Day 0.25 134.2 107.3 18.3 86.2 115.297.6 103.5 Day 0.5 112.7 95.2 10.3 94.0 86.1 93.1 90.2 Day 1 109.6 84.130.7 41.4 111.5 94.9 63.2 Day 3 92.7 55.4 24.0 34.5 38.0 65.2 46.4 Day 7151.0 344.0 334.8 110.1 906.7 400.0 152.3 Day 14 184.0 142.9 49.4 82.5113.5 132.7 201.7 Day 22 36.1 42.8 17.8 27.1 34.8 42.8 73.0 Day 28 36.348.7 8.5 43.4 54.3 54.0 55.4 Day 35 11.9 22.8 11.6 39.6 27.2 23.3 11.9Day 42 0.0 1.6 3.6 0.0 0.0 8.1 Day 45 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Day 500.0 1.6 3.5 0.0 0.0 0.0 7.9 Group III: 60 mg Day 0.04 56.7 77.6 17.8Risperidone 85.2 (15% Risperidone in 62.9 45% 82.5 65/35PLGHp(InV 100.60.37) and 55% NMP) Day 0.08 108.6 88.5 18.0 102.7 63.5 80.8 87.0 Day0.25 98.8 86.1 25.5 119.2 57.5 63.7 91.2 Day 0.5 85.5 82.5 21.7 112.751.7 79.7 82.9 Day 1 64.6 61.0 22.7 77.0 36.4 87.8 39.4 Day 3 36.7 30.98.6 37.3 19.6 37.1 23.7 Day 7 97.9 106.3 42.4 152.3 105.0 41.5 134.5 Day14 57.4 79.3 44.6 157.8 67.9 47.4 66.1 Day 22 37.5 30.3 8.5 32.2 19.738.9 23.2 Day 28 37.5 46.3 17.9 34.8 37.0 44.6 77.7 Day 35 29.4 28.7 7.136.5 17.9 32.9 26.5 Day 42 20.2 5.6 8.8 0.0 0.0 7.7 0.0 Day 45 0.0 0.00.0 0.0 0.0 0.0 0.0 Day 50 0.0 3.1 4.2 7.9 0.0 0.0 7.6 Group IV: 30 mgDay 0.04 81.4 60.0 17.9 Risperidone 73.6 (15% Risperidone 52.1 in 45%56.9 65/35PLGHp(InV 36.3 0.37) and 55% NMP) Day 0.08 88.1 72.4 19.5 96.557.7 68.7 50.8 Day 0.25 73.1 60.8 16.1 79.1 56.5 57.7 37.8 Day 0.5 86.558.2 20.7 71.6 45.1 52.8 35.0 Day 1 96.5 55.0 32.5 83.4 32.1 37.6 25.4Day 3 42.8 28.4 13.9 43.0 21.0 23.2 11.9 Day 7 24.2 34.0 21.1 23.3 15.668.9 37.9 Day 14 27.7 61.2 47.9 141.2 28.3 70.2 38.7 Day 22 26.2 23.16.8 18.7 13.3 28.6 28.7 Day 28 32.5 27.1 5.5 24.7 24.4 33.3 20.8 Day 3520.2 21.5 2.4 23.6 18.8 24.4 20.5 Day 42 17.5 5.1 7.8 8.2 0.0 0.0 0.0Day 45 17.6 3.5 7.9 0.0 0.0 0.0 0.0 Day 50 16.0 4.8 7.1 7.8 0.0 0.0 0.0

All implants were small or not found at Day 50. The risperidoneremaining in implants were analyzed using implant extraction and HighPerformance Liquid Chromatography method, results were summarized inTable 28.

TABLE 28 Risperidone Release at Day 50 After A Single SC Injection inRabbits % Mean % Test Time Risperidone Risperidone Standard ArticlePoint Released Released Deviation Group I: 50 mg Day 50 100 100 0RISPERDAL ® 100 CONSTA ® 100 100 100 Group II: 120 mg Day 50 100 100 0Risperidone 100 (15% Risperidone in 100 45% 65/35 PLGHp 100 (InV0.37)/NMP) 100 Group III: 60 mg Day 50 100 100 0 Risperidone 100 (15%Risperidone in 100 45% 65/35 PLGHp 100 (InV 0.37)/NMP) 100 Group IV: 30mg Day 50 100 100 0 Risperidone 100 (15% Risperidone in 100 45% 65/35PLGHp 100 (InV 0.37)/NMP) 100

None or minimal skin irritation was confirmed again in this study. Allimplants were small or not found at Day 50. All doses of theRisperidone/ATRIGEL® formulations showed an initial active risperidoneconcentration in plasma within the first 4 hours of the 50-day study.The second C_(max) was reached at day 7 for the 60 and 120 mgformulation. The plasma risperidone concentrations were doseproportional. The risperidone concentration exceeded 25 ng/mL throughday 35 in this rabbit study. Plasma risperidone concentrations fellbelow 25 ng/mL at day 42 and were near zero at day 50 for all 3 doses.

At one hour, the 50 mg RISPERDAL® CONSTA® injection showed plasmaconcentrations greater than 25 ng/mL. The plasma concentrations for this14-day product decreased to near zero until day 22 when the plasmarisperidone concentration exceeded 100 ng/mL. Plasma risperidoneconcentrations decreased to 12 ng/mL at day 35 and decreased to nearzero at days 42 through day 50.

The area under the plasma concentration curve (AUC_(Day 0-50)) for eachformulation, highest plasma risperidone concentration (C_(max)), andtime (TO for this rabbit study were shown in Table 29. Thepharmacokinetic profiles for all formulations injected in this rabbitstudy were shown in FIG. 15.

TABLE 29 Pharmacokinetic Parameters for EXAMPLE 2.3 C_(MAX)AUC_(0-50 DAYS) FORMULATION NG/ML T_(M) NG-DAY/ML 50 MG 102.5 DAY 221334.7 RISPERDAL ® CONSTA ® 120 MG 344.0 DAY 7 4102.7RISPERIDONE/ATRIGEL ® 60 MG 106.3 DAY 7 2159.5 RISPERIDONE/ATRIGEL ® 30MG 72.4 2 HOURS 1384.4 RISPERIDONE/ATRIGEL ®

Example 2.4

A second pharmacokinetic study in rabbits was conducted to confirm thedata in the previous 50-day rabbit study (EXAMPLE 2.3). The subcutaneousdoses in the rabbit were 30, 60, and 120 mg risperidone in the selectedformulation. The injection volumes into the rabbit were 0.2, 0.4, and0.8 mL. The study duration was 35 days with blood collection at 1, 2, 4,6, 8, and 12 hours and at 1, 4, 9, 16, 22, and 30 days via marginal earvein. At day 35, after blood collection by cardiac puncture the animalwas euthanized and the implant was removed for determination ofrisperidone remaining in the implant.

The plasma was analyzed following the Plasma SPE Extraction ProcedureFor Active Risperidone Plasma Analysis, described above. The activerisperidone concentrations were analyzed using the Reversed Phase HighPerformance Liquid Chromatography Method For The Quantization ofRisperidone And 9-Hydroxyrisperidone, described above. Activerisperidone concentrations at each time point were listed in Table 30.

TABLE 30 35-Day Active Risperidone Concentrations Plasma Mean Concen-Concen- Test Time tration tration Standard Article Point ng/ml ng/mlDeviation Group I: 120 mg Day 0.02 123.1 100.7 23.3 Risperidone 120.1(15% Risperidone 91.0 in 45% 103.3 65/35PLGHp(InV 66.1 0.37) and 55%NMP) Day 0.04 84.8 137.8 44.2 197.3 165.5 128.6 113.0 Day 0.08 179.9203.2 42.8 249.3 250.0 163.4 173.5 Day 0.16 217.8 257.7 39.5 317.2 262.2265.7 225.5 Day 0.25 301.4 277.0 33.9 292.8 309.2 234.3 247.1 Day 0.33162.7 236.3 79.2 234.6 345.6 278.9 159.6 Day 0.5 219.2 206.9 21.5 237.1203.3 188.1 186.6 Day 1 129.3 149.3 58.0 111.4 247.7 153.1 105.2 Day 4111.3 98.3 34.4 157.1 67.3 97.4 135.8 61.5 73.0 131.0 59.9 88.3 Day 9209.5 280.7 181.5 231.4 222.0 225.3 277.5 154.7 210.3 787.7 274.9 213.6Day 16 120.2 149.2 54.8 120.2 283.4 132.6 160.0 119.3 157.3 187.4 108.9103.1 Day 23 86.7 78.9 22.4 110.4 88.2 40.5 79.7 48.8 91.5 103.5 75.264.2 Day 30 28.3 30.2 14.1 21.7 41.8 0.0 31.5 30.7 38.5 48.5 41.9 19.4Day 35 0.0 4.9 9.1 0.0 0.0 0.0 0.0 18.9 0.0 5.5 24.6 0.0 Group II: 60 mgDay 0.02 95.5 89.5 9.2 Risperidone 98.6 (15% Risperidone 79.2 in 45%94.5 65/35PLGHp(InV 79.9 0.37) and 55% NMP) Day 0.04 158.2 94.6 39.456.5 76.0 78.0 104.1 Day 0.08 105.5 168.9 45.5 169.9 147.6 198.5 222.9Day 0.16 231.4 141.9 54.5 96.2 107.0 153.5 121.4 Day 0.25 148.1 164.721.1 141.7 190.4 161.1 182.0 Day 0.33 169.1 152.2 43.7 100.4 213.2 121.7156.9 Day 0.5 97.0 159.6 58.2 128.7 171.3 149.6 251.4 Day 1 90.7 95.433.6 55.3 139.1 73.9 117.8 Day 4 55.9 60.5 11.0 69.8 51.5 60.3 55.1 58.266.3 49.1 53.1 85.8 Day 9 166.5 188.8 110.9 215.0 142.4 119.2 110.2140.1 285.6 463.9 125.0 119.9 Day 16 105.2 96.1 36.7 101.2 131.6 94.5168.7 68.1 69.6 98.0 33.0 91.6 Day 23 74.8 48.6 36.5 27.3 66.5 35.7133.3 42.1 34.4 48.0 0.0 23.9 Day 30 26.1 20.0 15.6 0.0 40.3 23.7 18.521.6 0.0 41.7 0.0 27.6 Day 35 0.0 4.4 6.1 10.9 0.0 13.8 0.0 13.8 0.0 0.00.0 5.5 Group III: 30 mg Day 0.02 51.6 70.2 14.7 Risperidone 70.5 (15%Risperidone 91.4 in 45% 63.1 65/35PLGHp(InV 74.4 0.37) and 55% NMP) Day0.04 83.8 67.1 26.3 53.5 34.1 101.7 62.1 Day 0.08 62.4 94.5 26.2 132.179.8 93.8 104.4 Day 0.16 141.9 113.5 39.9 94.3 51.8 143.3 136.3 Day 0.2572.5 82.9 16.7 97.8 94.3 91.2 58.8 Day 0.33 145.5 106.5 30.7 103.9 59.7110.5 112.8 Day 0.5 84.0 85.4 14.6 101.7 73.5 98.8 69.1 Day 1 88.3 76.121.8 60.9 47.8 81.0 102.3 Day 4 43.0 53.3 27.8 38.3 42.8 47.0 72.7 45.537.8 126.1 48.2 31.5 Day 9 136.0 88.1 38.3 56.6 162.0 58.6 96.1 104.192.5 51.6 45.7 78.3 Day 16 28.0 51.8 16.5 53.3 55.9 64.5 35.6 86.3 42.942.9 47.3 60.9 Day 23 0.0 24.7 15.5 31.1 17.4 29.7 22.0 44.9 23.8 0.039.3 38.8 Day 30 0.0 19.0 8.7 23.2 9.0 21.9 19.7 24.8 25.2 17.2 19.229.8 Day 35 0.0 2.9 6.1 0.0 0.0 0.0 0.0 13.2 0.0 0.0 0.0 15.5

All implants were small at Day 35. Implant retrieval data were listed inTable 31.

TABLE 31 Active Risperidone Concentrations Test Time % Mean % StandardArticle Point Released Released Deviation Group I: 120 mg Day 35 100.099.8 0.3 Risperidone 15% Risperidone in 45% 100.0 65/35 PLGHp (InV0.37)/NMP) 100.0 100.0 100.0 99.2 100.0 100.0 99.4 100.0 Group II: 60 mgDay 35 99.7 99.8 0.3 Risperidone (15% Risperidone in 45% 100.0 65/35PLGHp (InV 0.37)/NMP) 100.0 98.9 99.9 99.8 100.0 100.0 100.0 100.0 GroupIII: 30 mg Day 35 100.0 99.5 0.8 Risperidone (15% Risperidone in 45%99.9 65/35 PLGHp (InV 0.37)/NMP) 99.9 99.9 100.0 99.1 99.9 99.0 99.897.4

None or minimal skin irritation was confirmed again in this study. Allimplants were small at Day 35. All doses of the Risperidone/ATRIGEL®formulations showed an initial burst of plasma risperidone within thefirst 8 hours of the 35-day study. The risperidone concentrations foreach dose were dose dependent and the plasma risperidone profile showeda second burst of risperidone at day 9 in this study for the 60 and 120mg risperidone doses. The risperidone concentration exceeded 25 ng/mLthrough day 30 in this rabbit study. Plasma risperidone concentrationsfell below 25 ng/mL at day 35 for all 3 doses of risperidone/ATRIGEL®.

The area under the curve (AUC_(Day 0-35)) for each formulation, highestplasma risperidone concentration (C_(max)) and time (T_(m)) for thisrabbit study were shown in Table 32. The pharmacokinetic profiles forall formulations injected in this rabbit study were shown in FIG. 16.

TABLE 32 Pharmacokinetic Parameters for EXAMPLE 2.4 C_(MAX)AUC_(DAY 0-35) FORMULA NG/ML T_(M) NG-DAY/ML 120 MG 280.7 DAY 9 4298.9RISPERIDONE/ATRIGEL ® 60 MG 188.8 DAY 9 2860.2 RISPERIDONE/ATRIGEL ® 30MG 113.5 4 HOURS 1654.4 RISPERIDONE/ATRIGEL ®

Example 3 Pharmacokinetics and Pharmacodynamics Studies in Dogs

The purpose of this study was to determine the pharmacokinetic profilesof risperidone/ATRIGEL® formulations and to evaluate the anti-emeticeffect in dogs. The selected Risperidone/ATRIGEL® formulation wasevaluated in EXAMPLE 3 for pharmacokinetic and pharmacodynamic in thedog. This dog preclinical study was conducted in male Beagle Dogs. Sixdogs per test article were injected subcutaneous with a full dose of thetest article at 30 or 60 mg risperidone. One group was injected with theATRIGEL® delivery system and one group, under anesthesia, was injectedintramuscularly with 2 mL of the RISPERDAL® CONSTA® formulation at 50 mgas negative and positive control respectively. The study duration was 45days with blood collection at 1, 2, 6, and 8 hours, and 1, 3, 7, 10, 14,21, 28, 35, 42, and 45 days. The pharmacodynamic study was alsoconducted at Day 1, 3, 7, 10, 14, 21, 28, 35, 42, and 45.

At specific time points, approximately 2-3 mL of blood was collected inK₃EDTA tubes from each dog. The plasma fraction was transferred tolabeled 5 mL plastic culture tubes and stored at −86° C. The plasma wasextracted following the Plasma SPE Extraction Procedure For ActiveRisperidone Plasma Analysis, described above. The active risperidoneconcentrations were analyzed using the Reversed Phase High PerformanceLiquid Chromatography Method For The Quantization of Risperidone And9-Hydroxyrisperidone, described above.

The active risperidone plasma concentration was calculated based on bothrisperidone and 9-hydroxyrisperidone. The active risperidone plasmaconcentration was calculated based on both risperidone and9-hydroxyrisperidone and was presented in Table 33.

TABLE 33 45-Day Active Risperidone Concentrations Mean Plasma Concen-Test Time Concentration tration Standard Article Point ng/ml ng/mlDeviation Group I: Day 0.04 5.1 7.7 2.7 RISPERDAL ® CONSTA ®, 50 mg, IM11.8 7.8 4.4 8.6 8.3 Day 0.08 5.7 7.5 3.5 8.3 11.7 2.3 10.8 6.4 Day 0.252.9 3.3 1.9 4.8 3.9 2.7 5.5 0.0 Day 0.33 2.5 2.8 1.6 4.0 3.6 1.9 4.5 0.0Day 1 0.5 0.9 0.7 1.3 0.6 0.9 2.1 0.0 Day 3 0.5 2.7 3.8 10.0 3.8 0.5 1.10.0 Day 7 2.9 2.7 2.8 6.8 0.0 5.1 1.2 0.0 Day 10 0.8 8.4 16.6 6.0 0.042.0 1.4 0.0 Day 14 2.0 11.4 21.6 9.2 0.4 54.9 1.7 0.5 Day 21 33.7 43.624.9 65.6 71.3 49.2 39.1 2.3 Day 28 98.5 103.6 57.6 112.8 92.3 56.8210.4 51.0 Day 35 35.0 50.9 70.0 43.7 0.0 12.8 190.3 23.7 Day 42 0.011.6 25.7 5.7 0.0 0.0 63.9 0.0 Day 45 0.0 4.8 11.8 0.0 0.0 0.0 28.8 0.0Group II: 45% Day 0.04 0.0 0.9 1.2 65/35 PLGH (InV 0.37) 0.0 and 55% NMP2.6 0.0 2.3 0.4 Day 0.08 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Day 0.25 0.00.0 0.0 0.0 0.0 0.0 0.0 0.0 Day 0.33 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Day1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Group III: 60 mg Day 0.04 4.9 33.331.6 Risperidone (15% RSP in 45% 2.2 65/35 PLGHp (InV 28.4 0.37)/NMP)54.5 85.0 24.7 Day 0.08 81.2 114.1 50.9 75.7 110.5 157.7 192.9 66.4 Day0.25 84.4 106.4 65.4 62.4 85.5 139.6 222.6 44.0 Day 0.33 84.8 95.2 56.463.2 122.7 74.9 193.4 32.0 Day 1 49.7 65.9 41.1 41.5 64.6 77.1 140.322.1 Day 3 36.0 54.7 33.2 52.6 44.1 79.5 105.0 11.0 Day 7 56.5 72.4 52.270.2 62.9 58.9 171.2 14.5 Day 10 60.9 104.4 110.8 134.3 25.8 55.1 316.633.7 Day 14 86.0 56.1 41.7 83.7 11.5 38.0 107.4 10.5 Day 21 14.8 7.9 6.315.2 2.7 6.0 8.7 0.0 Day 28 5.1 3.5 2.9 7.4 2.1 1.1 5.4 0.0 Day 13.3 8.36.5 35 11.3 11.4 0.0 13.8 Day 0.0 0.0 0.0 42 0.0 0.0 0.0 0.0 0.0 Day 0.00.0 0.0 45 0.0 0.0 0.0 0.0 0.0 Group IV: 30 mg Day 19.1 45.0 20.5Risperidone 0.04 (15% RSP in 45% 35.3 65/35 PLGHp (InV 32.7 0.37)/NMP)50.7 77.4 55.0 Day 20.7 54.0 37.6 0.08 22.4 37.3 78.2 117.7 47.8 Day16.0 45.5 32.6 0.25 18.3 48.3 41.3 106.2 42.7 Day 0.33 13.3 38.9 33.89.7 41.9 28.8 102.8 36.5 Day 1 10.9 30.6 28.6 13.2 34.6 16.0 86.4 22.3Day 3 16.3 36.1 25.2 6.2 44.9 26.0 76.2 46.9 Day 7 9.2 29.3 31.9 6.114.3 24.3 91.9 30.3 Day 10 20.1 51.5 54.4 4.9 32.1 77.7 150.5 23.8 Day14 3.8 27.1 31.9 5.1 38.0 9.4 86.9 19.5 Day 21 1.1 2.0 2.9 0.0 0.0 0.03.9 7.1 Day 28 0.0 0.6 1.1 0.0 2.8 0.8 0.0 0.0 Day 35 0.0 0.0 0.0 0.00.0 0.0 0.0 0.0 Day 42 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Day 45 0.0 0.00.0 0.0 0.0 0.0 0.0 0.0

In the afternoon at the specified time points each dog was injected withapomorphine and was monitored to determine the emetic effect of thedrug. A characteristic of risperidone in plasma is the prevention ofemesis.

Personnel evaluated injection sites at each time point for anyabnormalities including redness, bleeding, swelling, discharge,bruising, and Test Article extrusion. Additionally, personnel observedanimals post administration for signs of overt toxicity for the durationof the study.

The plasma was analyzed following the Plasma SPE Extraction ProcedureFor Active Risperidone Plasma Analysis, described above. The activerisperidone concentrations were analyzed using the Reversed Phase HighPerformance Liquid Chromatography Method For The Quantization ofRisperidone And 9-Hydroxyrisperidone, described above. None or minimalskin irritation was confirmed and consistent with the previous rabbitstudies.

The two doses of the risperidone/ATRIGEL® formulations showed an initialmaximum plasma risperidone concentration within the first 2 hours of the45-day study. The risperidone concentrations for each dose were dose,dependent and the plasma risperidone profile showed a second burst ofrisperidone at day 10 (51.0 ng/mL and 104.4 ng/mL) for the 30 and 60 mgrisperidone doses. The risperidone concentration exceeded 5 ng/mLthrough day 21 in this dog study for the 60 mg dose. Plasma risperidonelevels were less than 10 ng/mL from day 21 through day 35. There were nodetectable risperidone concentrations at day 42 and 45 for the 60 mgrisperidone formulation. The plasma risperidone of the 30 mgRisperidone/ATRIGEL® group showed less than 5 ng/mL at day 21 andrisperidone concentrations were near zero at days 28 through 45.

The 50 mg RISPERDAL® CONSTA® group (Group I) showed an initial plasmarisperidone concentration of 7.7 ng/mL. Plasma risperidoneconcentrations continued to be at or below this concentration until day14 when the risperidone concentration in plasma increased to a meanvalue of 11.4 ng/mL. The highest plasma risperidone concentrations(C_(max)) for this product were found at day 28, 104.4 ng/mL. The plasmarisperidone concentrations at day 42 decreased to 11.4 ng/mL and at day45 plasma risperidone was 4.8 ng/mL.

The area under the curve. (AUC_(Day 0-45)) for each formulation, highestplasma risperidone concentration (C_(max)) and time (T_(m)) for this dogstudy were shown in Table 34. The pharmacokinetic profiles for allformulations injected in this dog study were shown in FIG. 17.

TABLE 34 Pharmacokinetic Parameters for EXAMPLE 3.1 C_(MAX)AUC_(DAY 0-45) FORMULA NG/ML T_(M) NG-DAY/ML 120 MG 103.6 DAY 28 1561.1RISPERDAL ® CONSTA ® 60 MG 114.1 2 HOURS 1379.6 RISPERIDONE/ATRIGEL ® 30MG 54.0 2 HOURS 626.9 RISPERIDONE/ATRIGEL ®

The pharmacodynamics for risperidone in plasma were measured by theantiemesis effects of risperidone in plasma. At the time pointspreviously described, dogs were injected with an iv administration ofapomorphine. After apomorphine administration, the dog was observed for15 minutes for emesis and the dogs showing emesis were recorded aspositive. Results of this testing were recorded in Table 35.

All dogs in the ATRIGEL® group had emesis at all time points. Dogs inthe 30 mg dose of Risperidone/ATRIGEL® group showed no emesis throughday 21 of the study. At day 28, 33% of the dogs showed an antiemeticeffect. Dogs in this group at days 35 through 45 showed a 0-17%antiemetic effect. The 60 mg dose of Risperidone/ATRIGEL® showed noemesis through day 21 and the antiemetic effect was demonstrated in 83%of the dogs at day 28. The antiemetic effect was observed at 50-67% inthe dogs in this group from days 35 through 45. The 50 mg dose ofRISPERDAL® CONSTA® showed a variable antiemetic effect from day 1through day 21. The antiemetic effect was 100% for these dogs at days 28and 35. It decreased at days 42 and 45.

The pharmacokinetic profile for the dogs correlated with the observedanti-emetic effect. Higher plasma risperidone concentrations protectedthe dogs from emesis. The 30 mg Risperidone/ATRIGEL® formulation showed100% pharmacodynamic activity through Day 21 and decreased to 33% at Day28. At time points after Day 28, the antiemetic effect was zero and theplasma risperidone concentrations were not detectable. The 60 mgRisperidone/ATRIGEL® formulation was nearly 100% effective againstemesis through Day 28 and showed some activity until the end of thestudy (Day 45). The RISPERDAL® CONSTA® product had its highestanti-emetic activity from days 14 through 35 in this study. At days 42and 45 the pharmacodynamics activity had decreased.

TABLE 35 Pharmacodynamics Risperidone/ATRIGEL ® in Dogs % Dogs ShowingAntiemetic Effect using Apomorphine 50 MG 30 MG 60 MG RISPERDAL ®RISPERIDONE/ RISPERIDONE/ CONTROL TIME DAY CONSTA ® ATRIGEL ® ATRIGEL ®ATRIGEL ® 1 50% (3/6) 100% (6/6) 100% (6/6)  0% (0/6) 3 83% (5/6) 100%(6/6) 100% (6/6)  0% (0/6) 7 67% (4/6) 100% (6/6) 100% (6/6)  0% (0/6)10 50% (3/6) 100% (6/6) 100% (6/6)  0% (0/6) 14 83% (5/6) 100% (6/6)100% (6/6)  0% (0/6) 21 83% (5/6) 100% (6/6) 100% (6/6)  0% (0/6) 28100% (6/6)   33% (2/6) 83% (5/6) 0% (0/6) 35 100% (6/6)   17% (1/6) 67%(4/6) 0% (0/6) 42 67% (4/6)  17% (1/6) 50% (3/6) 0% (0/6) 45 33% (2/6) 0% (0/6) 50% (3/6) 0% (0/6)

Example 4 Second Pharmacokinetics and Pharmacodynamics Studies in Dogs

In concern of the low plasma risperidone concentrations and less than100% antiemetic effect at Day 28 revealed in the dog study of EXAMPLE 3,a second dog pharmacokinetic and pharmacodynamic study (EXAMPLE 4) wasconducted to determine if slight modifications to therisperidone/ATRIGEL® delivery system could reduce initial release andincrease the duration of drug release. For example, threeRisperidone/ATRIGEL® formulations using polymers other than theidentified 65/35 PLGHp (37K) were evaluated. The formulations include:(1) 60 mg Risperidone, (15% Risperidone in 45% 75/25 PLGHp(37K)/N-methyl-2-pyrrolidone), (2) 60 mg Risperidone, (15% Risperidonein 45% 80/20 PLGHp (42K)/N-methyl-2-pyrrolidone), and (3) 60 mgRisperidone, (15% Risperidone in 50% 65/35 poly(lactide-co-glycolide)(Dod) (19K)/N-methyl-2-pyrrolidone).

Six male Beagle dogs per test article were injected subcutaneous with afull dose of the test article at 60 mg risperidone. The study durationwas 45 days with blood collection at 1, 2, 6, and 8 hours, and 1, 3, 7,10, 14, 21, 29, 35, 42, and 45 days. The pharmacodynamics study was alsoconducted at Day 1, 3, 7, 10, 14, 21, 29, 35, 42, and 45. The bloodcollection/analysis and pharmacodynamic studies were conducted followingthe same procedures as described in EXAMPLE 3.

Personnel evaluated injection sites at each time point for anyabnormalities including redness, bleeding, swelling, discharge,bruising, and Test Article extrusion. Additionally, personnel observedanimals post administration for signs of overt toxicity for the durationof the study. None or minimal skin irritation was confirmed andconsistent with the previous studies.

All formulations showed an initial maximum plasma risperidoneconcentration within the first 6 hours of the 45-day study. The plasmarisperidone profile showed a second burst of risperidone at Day 10 (70.0ng/mL and 88.4 ng/mL) for Group I and III respectively. No second burstfor Group II. The plasma active risperidone concentrations exceeded 12ng/ml through Day 29 and maintained detectable risperidone levels at Day42 and 45 for all the formulations.

The pharmacokinetic profiles for all formulations injected in this dogstudy were shown in FIG. 18, detailed data presented in Table 36.

TABLE 36 45-Day Active Risperidone Concentrations Mean Plasma Concen-Test Time Concentration tration Standard Article Point ng/ml ng/mlDeviation Group I: 60 mg Day 0.04 74.9 69.3 30.3 Risperidone (15%risperidone in 91.9 45% 75/25 PLGHp 62.3 (37K)/NMP) 0.4 ml SC 110.8injection 49.9 25.8 Day 0.08 116.9 129.8 58.0 203.6 140.9 119.6 166.131.4 Day 0.25 48.4 109.2 58.4 165.3 165.3 109.4 136.9 29.9 Day 0.33115.6 93.4 51.2 49.2 164.4 125.4 78.8 27.1 Day 1 47.3 62.4 19.5 86.574.7 77.4 50.0 38.7 Day 3 17.2 53.5 36.4 41.6 95.1 103.3 34.4 29.2 Day 718.6 45.3 24.7 37.9 76.0 46.0 72.7 20.9 Day 10 27.2 70.0 55.1 47.0 89.352.5 173.1 30.8 Day 14 25.6 41.3 19.8 75.8 53.0 25.2 37.6 30.3 Day 2110.9 19.0 9.3 34.0 26.0 13.8 11.2 18.2 Day 29 8.0 13.4 8.9 25.5 23.8 9.96.6 6.4 Day 35 5.5 7.2 4.2 15.2 6.2 8.1 5.1 3.2 Day 42 8.1 7.5 5.1 14.66.2 4.6 11.4 0.0 Day 45 4.5 4.7 4.1 10.2 5.8 7.6 0.0 0.0 Group II: 60 mgDay 0.04 181.3 65.3 62.1 Risperidone (15% risperidone 90.5 in 45% 80/20PLGHp 37.5 (42K)/NMP) 0.4 ml SC 27.8 injection 35.4 19.2 Day 0.08 168.575.1 49.4 91.9 39.4 56.2 43.0 51.5 Day 0.25 120.4 85.4 26.1 85.3 53.272.4 112.2 69.0 Day 0.33 78.6 75.2 29.3 45.9 107.5 52.3 112.8 54.3 Day 1106.0 83.0 45.2 71.5 19.8 129.8 126.4 44.4 Day 3 76.1 35.3 20.8 29.615.8 30.8 28.8 30.9 Day 7 39.6 26.1 11.6 26.9 7.1 36.5 24.3 22.3 Day 1029.4 22.1 11.8 21.9 6.1 40.1 20.4 14.6 Day 14 20.3 22.6 13.9 11.0 14.341.0 38.7 10.1 Day 21 20.3 15.6 10.5 8.1 7.6 34.8 12.9 10.1 Day 29 17.021.7 11.1 14.1 19.2 39.5 30.5 10.1 Day 35 17.2 16.8 8.4 11.1 6.7 30.022.6 13.2 Day 42 10.0 6.2 5.2 7.1 1.2 13.7 0.0 5.5 Day 45 7.0 3.4 3.23.4 0.0 7.1 0.0 3.1 Group III: 60 mg Day 0.04 35.5 32.7 13.3 Risperidone(15% 56.1 risperidone in 50% 65/35 PLGHp 19.1 (D) (29K)/NMP) 25.4 0.4 mlSC 24.1 injection 35.9 Day 0.08 54.3 42.3 17.8 66.2 20.7 40.5 23.2 48.8Day 0.25 43.0 46.5 17.5 54.8 77.1 33.3 28.6 41.9 Day 0.33 55.0 41.8 10.041.0 43.4 50.3 30.8 30.5 Day 1 61.3 33.5 15.6 24.8 22.9 26.7 22.4 42.8Day 3 42.6 29.5 15.9 29.0 18.8 17.8 14.7 54.3 Day 7 25.1 36.7 33.3 25.823.2 37.5 7.0 101.8 Day 10 72.4 88.4 109.3 50.5 43.2 40.3 15.7 308.5 Day14 82.2 68.6 73.2 30.8 66.1 14.4 11.8 206.4 Day 21 32.9 26.5 15.1 9.543.6 20.2 11.0 41.9 Day 28 12.1 12.3 4.6 6.7 15.9 8.2 12.0 18.9 Day 356.9 8.0 4.7 4.8 14.6 9.8 1.3 10.6 Day 42 3.2 4.8 3.4 8.8 6.7 7.5 0.0 2.9Day 45 0.0 1.3 2.6 6.5 0.0 0.0 0.0 1.5

The area under the curve (AUC_(Day 0-45)) for each formulation, highestplasma risperidone concentration (C_(max)) and time (T_(m)) for this dogstudy were shown in Table 37.

TABLE 37 Pharmacokinetic Parameters for EXAMPLE 4 AUC_(DAY 0-45) C_(MAX)(NG- TEST ARTICLE (NG/ML) T_(M) DAY/ML) GROUP I: 60 MG RISPERIDONE 129.82 1270.7 15% RSP IN 45% 75/25 PLGHP HOURS (37K)/NMP GROUP II: 60 MGRISPERIDONE 85.4 6 973.3 15% RSP IN 45% 80/20 PLGHP HOURS (42K)/NMPGROUP IV: 60 MG RISPERIDONE 46.5 6 1339.1 15% RSP IN 45% 65/35 PLGP(D)HOURS (27K)/NMP

Table 38 showed the pharmacodynamic results of the study. The same dogin Group I threw up on Day 3 and Day 10 in 14-16 minutes afteradministration of apomorphine, another dog in this group showed emesison Days 42 and 45, all the other dogs remained healthy through out thestudy. All dogs showed anti-emesis through Day 45 in Group II except onedog threw up on both Days 42 and 45. These results indicate thatformulations Group I and II released risperidone slowly over time andremained at efficacious risperidone levels in dogs over 35 days.Starting from Day 42, active risperidone concentration in some animals(approximately 16.6%) started to drop and could not retain theanti-emetic effect. All dogs in Group III were healthy through Day 29, 3dogs showed no anti-emesis on Days 35 and 42, and 4 dogs on Day 45failed to show anti-emesis. These results indicate that FormulationGroup III was a one-month formulation which sustained releaserisperidone at an efficacious level over 29 days. However, Group IIshowed the best anti-emetic effect through out the study. Overall, allthree formulations sustained released efficacious amounts of risperidoneover time and showed a minimum efficacy of 29 days.

TABLE 38 Pharmacodynamics Risperidone/ATRIGEL ® in Dogs % Dogs ShowingAntiemetic Effect using Apomorphine 60 MG 60 MG 60 MG RISPERIDONERISPERIDONE RISPEIRDONE (15% (15% (15% RISPERIDONE IN RISPERIDONE INRISPERIDONE IN TIME 45% 75/25 PLGHP 45% 80/20 PLGHP 50% 65/35 PLG DAY(37K)/NMP) (42K)/NMP (DOD) (27K)/NMP 1 100% (6/6) 100% (6/6) 100% (6/6)3  83% (5/6) 100% (6/6) 100% (6/6) 7 100% (6/6) 100% (6/6) 100% (6/6) 10 83% (5/6) 100% (6/6) 100% (6/6) 14 100% (6/6) 100% (6/6) 100% (6/6) 21100% (6/6) 100% (6/6) 100% (6/6) 29 100% (6/6) 100% (6/6) 100% (6/6) 35100% (6/6) 100% (6/6)  50% (3/6) 42  83% (5/6)  83% (5/6)  50% (3/6) 45 83% (1/6)  83% (5/6)  33% (2/6)

Example 5 Third Pharmacokinetics and Pharmacodynamics Studies in Dogs

The purpose of this study was to provide oral vs. risperidone/ATRIGEL®pharmacokinetic data to verify dosing in humans. For example, aRisperidone/ATRIGEL® formulation containing 15% Risperidone suspended ina delivery vehicle of 45% 80/20 PLGHp (42K)/N-methyl-2-pyrrolidone wasselected from EXAMPLE 4 and further evaluated in this pharmacokineticand pharmacodynamic dog study. Three test groups based on this selectedformulation delivering 60, 90, or 120 mg risperidone (Group IV, V, andVI) were tested and compared to three control groups, RISPERDAL® Tabletscontaining 2, 3, or 4 mg risperidone (Group I, II, and III).

Six dogs per test article in this study were injected subcutaneous withapproximately 400, 600, and 800 μl of the identified formulation, whichdelivered approximately 60, 90, and 120 mg of risperidone respectively.Six dogs per control article received an oral tablet daily for 35 days.The study duration was 56 days with blood collection at 1, 2, 4, 6, 8,and 12 hours, and 1, 3, 7, 10, 14, 21, 28, 35, and 42 for all sixgroups. Blood was also collected on Day 49 and 56 for ATRIGEL® groups.The pharmacodynamics study was conducted at Day 20, 24, 30, and 35. Theblood collection/analysis and pharmacodynamic studies were conductedfollowing the same procedures as described in EXAMPLE 3.

Personnel evaluated injection sites at each time point for anyabnormalities including redness, bleeding, swelling, discharge,bruising, and Test Article extrusion. Additionally, personnel observedanimals post administration for signs of overt toxicity for the durationof the study. None or minimal skin irritation was confirmed andconsistent with the previous studies.

Overall, Groups I to III (RISPERDAL® tablet groups) showed the plasmaC_(max) at 1 hour after administration, and reached steady plasma basallevels (C_(min)) from Day 7 to Day 35 (FIG. 19 and Table 39). TheC_(min) of Group I to III from Day 7 to Day 35 were 9.8, 17.3, and 27.2ng/ml respectively. Groups I to III showed decreases in plasmarisperidone concentration to approximately 3 ng/ml at Day 42 after thelast oral dose on Day 35. The plasma risperidone C_(max) levels andbasal levels C_(min) for the three groups were determined to be directlydose related.

TABLE 39 45-Day Active Risperidone Concentrations Plasma Mean Concen-Concen- Test Time tration tration Standard Article Point ng/ml ng/mlDeviation Group I: Day 0.04 125.2 104.6 45.1 RISPERDAL ® tablet, 2 mgoral, daily for 34.7 35 days 157.6 130.9 111.2 68.1 Day 0.08 134.6 95.261.4 6.6 172.9 125.2 86.0 45.9 Day 0.16 76.2 55.9 34.5 4.4 87.7 89.448.4 29.3 Day 0.25 47.8 33.9 22.4 0.0 45.8 60.5 32.9 16.1 Day 0.33 41.424.8 15.6 9.7 26.8 44.4 18.8 7.8 Day 0.5 16.7 12.4 8.7 1.6 15.0 24.813.0 3.4 Day 1 9.3 5.6 3.7 3.2 4.7 9.5 6.7 0.0 Day 3 10.3 3.4 4.2 0.0**269.2 3.2 3.6 0.0 Day 7 20.8 12.0 9.6 22.6 **159.7 10.7 6.0 0.0 Day 103.9 8.6 10.2 27.8 2.5 11.7 5.7 0.0 Day 14 10.9 11.6 9.4 24.5 2.0 15.516.8 0.0 Day 21 11.0 9.1 9.3 23.9 1.5 15.0 3.4 0.0 Day 28 8.5 6.0 4.310.3 2.7 10.3 4.1 0.0 Day 30 12.9 69.6 67.6 1 hour 85.2 177.1 13.7 *58.9 Day 30 6.6 45.0 44.6 2 hour 71.6 108.9 5.8 * 31.8 Day 30 5.3 37.636.8 4 hour 78.4 76.7 9.2 * 18.3 Day 30 4.4 31.4 32.9 6 hour 67.7 67.07.9 * 9.8 Day 35 11.0 11.6 8.1 25.6 6.0 15.6 8.3 3.1 Day 42 0.0 3.3 2.14.6 3.1 6.3 3.2 2.8 Group II: Day 0.04 * 119.4 19.7 RISPERDAL ® tablet,3 mg oral, daily 117.9 for 35 days 132.7 * 134.9 92.2 Day 0.08 * 98.123.8 119.0 81.8 * 118.0 73.7 Day 0.16 * 62.1 17.9 76.2 41.9 * 78.2 52.3Day 0.25 * 37.6 16.6 59.3 19.1 * 38.0 34.0 Day 0.33 * 30.6 17.3 38.213.9 * 51.2 19.1 Day 0.5 * 24.4 16.3 35.9 5.7 * 40.0 16.1 Day 1 * 10.88.8 17.4 0.0 * 18.6 7.4 Day 3 11.6 13.9 16.5 43.1 0.0 4.1 22.4 2.2 Day 70.0 17.5 22.5 58.9 0.0 25.2 14.6 6.1 Day 10 2.5 18.0 20.7 55.5 0.0 26.215.4 8.4 Day 14 10.7 21.4 17.0 52.1 12.6 30.1 15.6 7.1 Day 21 10.9 15.614.8 40.4 0.0 25.6 10.7 6.0 Day 28 10.9 14.9 14.7 40.3 0.0 23.9 8.5 5.9Day 30 180.6 123.8 79.1 1 hour 249.5 94.2 25.0 104.5 88.9 Day 30 157.8110.1 71.3 2 hour 226.2 64.1 28.1 101.1 83.4 Day 30 129.5 95.3 53.0 4hour 179.4 36.0 101.3 71.5 54.3 Day 30 94.3 92.7 70.0 6 hour 163.5 11.6186.9 63.3 36.5 Day 35 12.3 16.2 9.3 25.0 3.3 28.7 16.0 11.7 Day 42 2.92.9 1.7 5.0 3.1 3.9 0.0 2.4 Group III: Day 0.04 348.9 353.8 132.2RISPERDAL ® tablet, 4 mg oral, daily 439.4 for 35 days 489.7 * 347.1143.8 Day 0.08 195.0 265.3 110.6 316.7 378.0 * 328.6 108.2 Day 0.16 88.3176.6 90.3 240.7 272.1 * 208.1 73.7 Day 0.25 33.4 87.8 59.4 176.2120.7 * 55.7 52.8 Day 0.33 13.6 89.9 64.5 104.8 175.6 * 116.1 39.2 Day0.5 4.9 64.2 47.3 75.6 123.3 * 88.2 29.2 Day 1 1.8 25.9 19.9 26.4 50.6 *39.3 11.5 Day 3 0.0 35.7 38.6 95.8 65.6 3.4 38.7 10.7 Day 7 0.0 32.927.7 37.6 61.2 14.1 68.7 15.5 Day 10 0.0 29.9 34.9 10.1 68.4 4.0 79.717.2 Day 14 1.8 28.5 29.3 2.1 56.0 16.7 72.6 21.7 Day 21 1.7 22.8 18.935.4 17.3 11.5 54.2 16.7 Day 28 0.0 25.2 19.2 41.0 45.9 9.5 39.3 15.7Day 30 233.1 237.7 87.7 1 hour 304.9 247.5 178.6 353.9 107.9 Day 30160.6 274.7 102.7 2 hour 311.6 369.7 310.0 363.6 132.7 Day 30 75.8 208.797.2 4 hour 263.3 266.0 202.9 329.0 115.0 Day 30 28.6 142.5 82.5 6 hour207.9 215.9 102.9 219.5 80.2 Day 35 0.0 23.9 20.1 25.5 37.7 9.2 55.116.1 Day 42 0.0 2.9 2.3 0.0 5.2 3.2 4.8 4.0 Group IV: 60 mg Day 0.0448.8 82.8 38.7 Risperidone (15% risperidone 107.4 in 45% 80/20 PLGHp117.8 (42K)/NMP) 0.4 ml SC 127.7 injection 45.8 49.2 Day 0.08 55.4 95.339.1 117.0 137.0 132.4 83.0 47.1 Day 0.16 39.9 95.0 43.2 105.1 144.4125.0 111.4 43.9 Day 0.25 27.2 82.6 46.1 79.7 155.6 102.3 90.2 40.3 Day0.33 27.9 75.3 43.5 76.7 136.2 105.1 81.4 24.6 Day 0.5 18.9 49.1 31.923.1 98.0 72.7 55.8 26.4 Day 1 22.0 52.5 22.6 45.7 78.4 71.3 65.1 32.5Day 3 1.5 30.6 23.4 30.0 66.8 47.6 21.2 16.8 Day 7 5.6 32.6 29.4 21.688.0 40.9 20.5 18.7 Day 10 16.3 27.1 16.1 34.1 56.3 20.2 23.5 12.4 Day14 5.3 28.6 15.4 31.6 49.6 30.1 37.0 17.9 Day 21 11.0 23.1 10.7 24.529.8 27.9 36.1 9.4 Day 28 15.1 39.0 29.7 22.2 20.9 47.5 94.8 33.3 Day 3025.0 37.4 24.3 1 hour 17.9 35.2 61.5 72.2 12.7 Day 30 25.2 44.9 33.3 2hour 17.9 29.9 73.0 99.4 24.0 Day 30 17.5 40.3 32.8 4 hour 19.5 19.082.1 83.2 20.7 Day 30 23.4 34.9 25.6 6 hour 21.4 13.7 69.7 65.5 15.7 Day35 12.6 21.8 13.8 12.4 13.7 44.1 34.1 13.9 Day 42 16.3 20.2 6.5 19.015.8 22.3 32.3 15.3 Day 49 16.5 14.3 3.0 13.3 15.7 9.7 18.0 12.3 Day 568.6 11.0 3.0 7.7 15.1 9.0 12.2 13.3 Group V: 90 mg Day 0.04 150.1 102.844.3 Risperidone (15% risperidone 55.2 in 45% 80/20 PLGHp 70.8(42K)/NMP) 0.6 ml SC 147.9 injection 63.4 129.3 Day 0.08 185.0 116.454.2 58.6 62.4 172.8 94.6 124.7 Day 0.16 139.5 105.2 58.5 61.1 47.9204.1 74.7 103.9 Day 0.25 111.8 87.3 56.5 53.9 47.3 191.6 49.4 69.8 Day0.33 88.6 76.7 55.3 46.5 47.8 184.2 40.8 52.5 Day 0.5 76.6 49.4 39.921.4 21.6 118.7 27.0 30.9 Day 1 91.6 61.9 44.8 40.0 27.7 139.0 24.6 48.8Day 3 38.0 29.5 21.2 13.8 12.4 66.9 14.6 31.5 Day 7 39.9 33.0 29.9 13.310.2 89.0 13.9 31.5 Day 10 31.7 35.0 27.2 28.8 7.3 86.5 19.6 36.2 Day 1440.7 31.8 21.8 25.0 10.5 71.6 20.0 23.1 Day 21 38.8 24.0 20.1 17.1 13.157.8 7.6 9.4 Day 28 45.3 33.6 24.2 33.8 15.1 74.0 27.7 5.6 Day 30 41.436.1 26.2 1 hour 32.5 14.5 84.4 12.2 31.4 Day 30 39.2 40.8 29.8 2 hour36.7 24.6 99.1 16.0 29.3 Day 30 40.0 35.7 32.5 4 hour 29.9 17.2 97.3 4.625.1 Day 30 42.0 33.9 31.8 6 hour 27.9 12.0 93.5 5.2 23.1 Day 35 50.737.9 25.2 44.1 23.5 77.4 5.1 26.8 Day 42 56.5 33.2 26.2 14.1 17.6 74.410.2 26.7 Day 49 37.7 22.6 20.8 9.4 9.9 54.8 10.5 13.3 Day 56 20.4 18.88.6 8.8 11.7 30.6 15.2 25.8 Group VI: 120 mg Day 0.04 108.1 163.6 53.9Risperidone (15% risperidone 159.6 in 45% 80/20 PLGHp 158.0 (42K)/NMP),0.8 ml SC 252.2 injection 111.4 192.5 Day 0.08 130.1 180.1 64.0 154.4250.5 271.3 123.9 150.3 Day 0.16 134.4 161.0 53.0 146.8 229.4 221.7 96.3137.1 Day 0.25 117.3 133.4 50.8 117.7 201.8 184.3 64.0 115.3 Day 0.3398.9 110.4 45.0 86.9 175.4 148.5 49.3 103.6 Day 0.5 134.8 97.7 47.9 42.4143.6 35.5 130.4 99.4 Day 1 91.5 91.3 34.3 63.3 115.8 126.9 38.5 112.0Day 3 51.2 52.1 22.4 31.9 75.1 58.5 20.4 75.3 Day 7 27.8 41.3 22.5 35.975.4 45.0 9.9 53.8 Day 10 43.1 48.6 22.9 45.4 89.6 43.3 19.3 50.9 Day 1442.3 58.6 32.2 48.2 78.5 107.3 13.5 61.6 Day 21 44.2 46.6 22.1 14.6 62.076.5 30.5 51.6 Day 28 44.0 53.7 39.6 16.4 84.3 116.1 15.2 46.5 Day 3035.2 50.1 28.2 1 hour 26.4 91.0 78.1 23.3 47.0 Day 30 35.1 60.1 36.3 2hour 30.9 114.9 91.8 27.1 60.6 Day 30 35.8 58.5 38.7 4 hour 29.7 125.081.0 24.0 55.6 Day 30 35.9 55.8 37.1 6 hour 21.9 117.0 78.8 23.2 57.9Day 35 47.6 52.5 24.9 26.2 94.1 53.1 29.8 64.3 Day 42 48.8 52.7 25.322.0 57.7 71.6 27.9 88.1 Day 49 45.2 52.5 24.9 19.5 54.3 74.6 17.6 41.4Day 56 24.9 52.7 25.3 21.0 33.7 23.5 13.5 29.9 * These dogs probablyspilled the pills they received on that day since no risperidone or 9-OHrisperidone was detected at all hourly time points. **Data not includedin mean calculations.

Groups IV to VI (Risperidone/ATRIGEL® groups) reached plasma risperidoneC_(max) at approximately 2 hours post injection, and reached steadystate (Css) in the dog plasma from Day 3 until Day 42 (FIG. 20). Thesteady state plasma risperidone levels (Css) of Groups IV to VI from Day3 to Day 42 were 28.9, 32.7, and 50.7 ng/ml, respectively. The plasmarisperidone levels decreased slowly from Day 49 to 56 for all threeATRIGEL® groups. The C_(max) and steady state plasma levels (Css) weredose dependent.

FIG. 21 showed the pharmacokinetics comparison between Group I (2 mgRISPERDAL® group) and Group IV (60 mg Risperidone/ATRIGEL® JO group).The C_(max) (104.6±45.1 ng/ml) of Group I was higher than that of GroupIV (95.3±39.1 ng/ml), however the C_(min) (9.8 ng/ml) was lower than Cssof Group IV (28.9 ng/ml) from Day 1 to Day 42, even lower than theconcentration at Day 49 (14.3 ng/ml) and Day 56 (11.0 ng/ml). If theC_(max) and C_(min) plasma risperidone levels of the marketed 2 mgRISPERDAL® tablet formulation indicate efficacy for this dose level,this study indicated that the active plasma risperidone concentrationsreleased from the Risperidone/ATRIGEL® formulation meets efficacyrequirements throughout 56 days of the study.

The same conclusion could be drawn from the comparison between Group II(3 mg RISPERDAL® group) and Group V (90 mg Risperidone/ATRIGEL® group),as well as the comparison between Group III (4 mg RISPERDAL® group) andGroup VI (120 mg Risperidone/ATRIGEL® group). The pharmacokinetic datawere graphed in FIGS. 22 and 23.

On Day 30, an additional 6-hour pharmacokinetics study was conducted inall six groups, and the results of Group I to III were compared with6-hour pharmacokinetic profiles on Day 0 (FIG. 24). For Group I and II,plasma risperidone C_(max) was reached 1 hour after dosing, Group IIIshowed the plasma risperidone C_(max) at 2 hours post dosing. For GroupIV to VI, plasma concentrations stayed at steady state level (Css) atall time points. As indicated in FIG. 24, the pharmacokinetic profilesof Groups I to III on Day 30 paralleled the pharmacokinetic profiledetermined on Day 0.

WinNonlin version 5.0.1 software from PharSight was used in the AUC andt½ calculation in this report. A non-compartmental model withextravascular input for plasma data and linear trapezoidal calculationswas used. The total AUC_(Day 0-56) of ATRIGEL® groups were calculatedbased on the mean plasma concentrations obtained at each time point. Thetotal AUC_(Day 0-42) of RISPERDAL® groups were predicted using simpleaddition for 35 days based on the mean pharmacokinetics data on Day 0,and assuming the plasma risperidone concentration reached C_(min) at Day2. This prediction overestimated the total AUC since the steady stateC_(min) was not reached until Day 7 in this study. However, thedifferences would be acceptable as risperidone is a quick absorption andslow elimination drug. Also the plasma levels on Day 2 to Day 7 werevery close to the C_(min), so that the simple addition would not changethe pharmacokinetic profiles following each individual daily dosing.

TABLE 40 Pharmacokinetic parameters of each group in EXAMPLE 5 DoseC_(max) T_(m) C_(24hr) C_(min) of C_(ss) of normalized at at atRISPERDAL ® ATRIGEL ® AUC_(Day 0-1) AUC_(Day 0-42) AUC_(Day 0-56)NAUC_(Day 0-42) Day 0 Day 0 Day 0 groups groups ng · day/ ng · day/ ng ·day/ t_(1/2) ng · day/ ng/ml hours ng/ml ng/ml ng/ml ml ml ml day ml ·mg Group I, 2 mg oral 104.6 1  5.6  9.8 NA 26.2 1108.4 NA 0.44 15.8tablet Group II, 3 mg oral 119.4 1 10.4 17.3 NA 33.8 1483.2 NA 0.44 14.1tablet Group III, 4 mg oral 353.8 1 19.9 27.2 NA 91.8 3378.6 NA 0.3824.1 tablet Group IV, 60 mg  95.3 2 NA 28.9 63.1 1243.3 1417.6 NA 20.9Risperidone/ ATRIGEL ® Group V, 90 mg 116.4 2 NA 32.7 69.1 1421.5 1702.6NA 15.9 Risperidone/ ATRIGEL ® Group VI, 120 mg 180.1 2 NA 50.7 111.72238.9 3049.2 NA 19.0 Risperidone/ ATRIGEL ®

Table 41 showed the pharmacodynamic results of the study. The emesisstudy was conducted approximately 5 hours after the daily tablet dose.In Group I, one dog at each time point on Day 20, Day 24, and Day 30vomited after administration of apomorphine, all the other dogs inGroups II through VI showed anti-emesis through Day 35. These resultsindicated that 2 mg RISPERDAL® showed marginally efficacy while all theother groups were effective to prevent apomorphine induced emesis.

TABLE 41 Pharmacodynamics Risperidone/ATRIGEL ® in Dogs % Dogs ShowingAntiemetic Effect using Apomorphine GROUP I GROUP II GROUP III TIME 2 MG3 MG 4 MG DAY RISPERDAL ® RISPERDAL ® RISPERDAL ® 20 83% (5/6) 100%(6/6) 100% (6/6) 24 83% (5/6) 100% (6/6) 100% (6/6) 30 83% (5/6) 100%(6/6) 100% (6/6) 35 100% (6/6)  100% (6/6) 100% (6/6) GRJOUP IV GROUP VGROUP VI 60 MG 90 MG 120 MG RISPERIDONE/ RISPERIDONE/ RISPEIRDONE/ATRIGEL ® ATRIGEL ® ATRIGEL ® 20 100% (6/6) 100% (6/6) 100% (6/6) 24100% (6/6) 100% (6/6) 100% (6/6) 30 100% (6/6) 100% (6/6) 100% (6/6) 35100% (6/6) 100% (6/6) 100% (6/6)

Group IV, the relevant comparison to 2 mg RISPERDAL®, 60 mgRisperidone/ATRIGEL® formulation group remained at efficaciousrisperidone levels in dogs over 35 days. These results stronglysuggested that Risperidone/ATRIGEL® Formulations sustained releasedrisperidone over time and demonstrated better efficacy than relevantcomparison tablet groups.

Overall, all three Risperidone/ATRIGEL® formulations sustained releasedrisperidone into the plasma over time, and maintained steady stateplasma risperidone concentrations after the initial burst of risperidonein plasma until Day 42. Furthermore, the plasma levels of risperidone indogs were effective to maintain dogs free from emesis through Day 35 ofthe study. In addition, this is the first pre-clinical study to utilizeγ-irradiation to produce sterilized risperidone in the B syringe.

Example 6 Comparative Examples Using Non-PLGH Polymers Solubility ofRisperidone in the ATRIGEL® Delivery System Solvents

Risperidone as a dry powder was added to two of the solvents used in theATRIGEL® Delivery System at various concentrations until the limits ofsolubility were obtained.

Preparation of Formulations

The various ATRIGEL® formulations evaluated with risperidone wereprepared by two methods: (1) weighing specific amounts of risperidoneand solvent into glass vials, stirring for approximately five (5)minutes, and adding the biodegradable polymer; and (2) weighing specificamount of biodegradable polymer and solvent into glass vials, stirringuntil the polymer was dissolved, and adding the amount of risperidone.

In Vitro Formulation Release

Each formulation was run in triplicate with the following protocol: A 5mL aliquot of phosphate buffered saline (PBS) prepared with 0.02% sodiumazide adjusted to pH 7.4 was pipetted into a clean 8 mL amber vial. Thevials containing the PBS solution were conditioned at 37° C. forapproximately 2 hours in a shaker bath. The vials were removed from theshaker bath and quickly tarred on an analytical balance capable ofweighing to an accuracy of 0.1 mg. The formulation to be tested wasplaced into a 1 ml polypropylene syringe and a sample (30 to 60 mg) wasprecipitated into the PBS receiving fluid. The vial was reweighed andthe amount of formulation weighed into the vial was recorded. The vialwas placed into the 37° C. shaker bath with a sealed Teflon cap.

The release solutions were removed after day 1, 2, 3, 5, and 7 days, andat 48 to 72 hour intervals after the first seven days of the releasetesting. The release solutions were stored at 5° C. until they wereanalyzed. The remaining PBS solution in each vial was removed byinversion, the vial dried by air, 5 mL of PBS solution was pipetted intothe vial and the vial was returned to the shaker bath at 37° C. untilthe next time interval. A placebo formulation of polymer and thebiocompatible solvent was prepared to evaluate interferences indetermination of the risperidone by ultraviolet analysis.

Methods of Analysis

The concentration of risperidone in the receiving fluids was determinedby ultraviolet spectroscopy at 275 nm. Standards of risperidone wereprepared by dissolving approximately 11 mg (nearest 0.1 mg) ofrisperidone in 100 mL of the PBS solution. Appropriate dilutions weremade for a 4 point curve. Linear regression analysis of the standardsresulted in a slope of 37.6, a y-intercept of −0.6, and a regressionanalysis of 0.9999. The standards appear to be stable at 5° C. forapproximately 14 days. The limit of detection for the risperidone is 1.6μg/mL by this method. An ultraviolet scan of a 56.3 μg/mL of risperidonein PBS has a maximum absorption at 276 nm. There is no apparentinterferences from the two biocompatible solvents,N-methyl-2-pyrrolidone or ethyl lactate, in the ultraviolet analysis at275 nm.

An High Performance Liquid Chromatography method for the analysis ofrisperidone uses an RP18 Hypersil ODS cartridge HP (Hewlett-Packard)with 3 μm particle size. The column was a 10 cm RP18 Hypersil ODS columnwith 3 μm particle size. The column uses a mobile phase of 65% 0.01MNH₄H₂PO₄ brought to pH 8 with diisopropylamine and 35% acetonitrile. Theflow rate was 1.5 mL/min and the detection of drug was by ultravioletspectrophotometry. Retention time for the risperidone was between 2.30and 2.45 minutes,

Analysis of Polymer Formulations for Risperidone

Mass balance of the risperidone in the residual polymer after releasetesting of formulation was performed by dissolving the residual polymerin a 25% acetonitrile/75% methanol solution, diluting to volume with thesame solvent and analyzing by ultraviolet spectrophotometry at 275 nm ofHigh Performance Liquid Chromatography. Determination of the risperidonein the original formulation stored at 5° C. was performed by dissolvinga known weight of formulation in a solvent mixture of 25%acetonitrile/75% methanol followed by High Performance LiquidChromatography analysis.

Preparation of Pilot Scale Risperidone Formulations

The polymer/risperidone formulations were prepared for in vivoevaluation in 20 gram batches and for stability/sterilization testing in100 gram batches. Four formulations at the 20 gram scale were preparedusing glass equipment in a class 10,000 clean room area for the in vivotrial. The process of manufacturing used the addition of the risperidoneto the solvent on a weight basis. After sufficient stirring(approximately 90 minutes) the polymer was added to the solution ormixture and stirred for 2 to 16 hours. Generally the formulationcontaining the lactide/glycolide copolymers (PLG) stirred for about 2hours. Formulations using the lactide/caprolactone copolymers (PLC)stirred up to 16 hours for dissolution of the polymer into the mixture.The formulations were filled into 10 ml polypropylene syringes andcapped. All syringes were maintained at 5° C. until resting wasinitiated.

Eight (8) 100 gram formulations for stability/sterility testing wereprepared using a laboratory Ross mixer for preparation. Risperidoneconcentrations used in these ranged from 5% to 20% by weight.Formulations were prepared in general by adding a known weight ofrisperidone to the weighed solvent in the Ross mixer bowl. Aftersufficient mixing time the polymers were added to the mixture orsolutions and mixed until the polymer was dissolved. The exception tothese standard preparations was the poly(lactide-co-caprolactone)formulations. The poly(lactide-co-caprolactone) polymers have a longerdissolution time. Therefore, it was determined that mixing thepoly(lactide-co-caprolactone) polymer with the solvent(N-methyl-2-pyrrolidone or ethyl lactate) 16 to 24 hours prior toformulation preparation was typically used to prepare the risperidoneformulations. The risperidone was added to the polymer/solvent solutionas a dry powder in all cases where this procedure was used.

After completion of the formulation preparations, the entire mixture orsolution was transferred into glass jars until they were prepared forsterility evaluation by gamma radiation and/or stability evaluation at−6°, 5°, and 25° C.

Sterilization of Risperidone/Polymer Formulations

The eight formulations prepared for testing were sterilized in glassvials and gamma resistant polypropylene copolymer syringes using variousdose levels of irradiation. In addition to the formulations, risperidoneas a dry powder was also sterilized in syringes and glass vials as wellas a 5% solution of risperidone in ethyl lactate orN-methyl-2-pyrrolidone. Sterilization of ethyl lactate was alsoperformed.

Animal Studies

Three in vivo studies were conducted with the risperidone/polymerformulations developed in this program. The first study was carried outby injecting four formulations intramuscularly into dogs using 18 gaugeneedles. The injection volumes of the different formulations wereadjusted to give approximately 2.5 mg/kg of risperidone in each animal.Samples of blood were withdrawn from each dog an Day 1 at 0, 1, and 5hours followed by additional samples taken on Days 2, 5, 8, 12, 15, 19,and 22 if suggested by the apomorphine challenge. In this test,apomorphine is injected at different time intervals and the lack ofemesis in the dogs indicates that the plasma levels are above thethreshold for antipsychotic activity. The samples of blood are analyzedfor risperidone and its major metabolite, 9-hydroxyl risperidone, byHigh Performance Liquid Chromatography methods.

The second study was also conducted using the same methods describedabove. In this study, the two most promising formulations by in vitrorelease data, were tested. The third study was conducted by using fourformulations developed for evaluations. In this study, the fourformulations were injected intramuscularly into rats. The rats weresacrificed at 6 and 24 hours after injection and on Days 3, 5, and 7.The polymer implants were retrieved, residual tissue was cleaned off thepolymer implants, and they were lyophilized. After lyophilization, thepolymer implants were ground and extracted with 25/75acetonitrile/methanol. The extracting solution was filtered and thesolutions analyzed for risperidone content by ultraviolet spectroscopy.The percent release of risperidone was calculated based upon the amountsof polymer injected and retrieved.

Results and Discussion

The results and discussion section is organized by the solvent used todevelop the liquid ATRIGEL® Delivery System for risperidone.

ATRIGEL® Delivery System with N-Methyl-2-Pyrrolidone as theBiocompatible Solvent

Solubility Limits:

The limits of solubility tests showed that risperidone was soluble inN-methyl-2-pyrrolidone up to 5% by weight. Therefore any ATRIGEL®formulation containing the target quantity of risperidone (150 mg=7.5%by weight) would be a suspension. It was also found that the order ofaddition was of interest for the ATRIGEL® System withN-methyl-2-pyrrolidone. If the risperidone was first dissolved inN-methyl-2-pyrrolidone, followed by the addition of polymer, theformulations were solutions up to 5% by weight risperidone. If therisperidone was added to the already formed polymer solution, the drugwas not soluble at the 5% by weight level.

In Vitro Release:

A number of polylactides (PLA), lactide/glycolide copolymers, andlactide/caprolactone copolymers were used with N-methyl-2-pyrrolidone todevelop formulations for controlled release of risperidone. Theconcentration of polymer and the concentration of drug used in theseformulations was varied. Also, additives were employed in efforts toaffect the release rates. The sixty-three (63) formulations preparedwith N-methyl-2-pyrrolidone and evaluated are given in Table 41.

TABLE 41 Polymer Formulations Using N-Methyl-2-Pyrrolidone Polymer %Polymer % Drug Load Additives 50/50 PLG (0.35) 40 5, 10, 20 None 50/50PLG (0.35) 30 5, 10, 15, 20 None 50/50 PLG (0.19) 25 5, 10, 20 None50/50 PLG (0.19) 40 10 None 50/50 PLG (0.52) 25 5, 10, 20 None 85/15 PLG(0.24) 25 5, 10, 20 None 65/35 PLG (0.23) 25 5, 10, 20 None 65/35 PLG(0.41) 25 10, 20 None 75/25 PLC (0.74) 40  5, 10 None 50/50 PLC (0.63)40  5, 10 None 75/25 PLC (0.74) 25 10, 20 None 50/50 PLC (0.63) 25 10,20 None PLA (0.24) 40 5, 10, 20 None PLA (0.36) 40  5, 10 None PLA(0.22) 30 10 None PLA (0.24) 25 20 None PLA (0.22) 25 20 None PLA (2000)25 20 None PLA (2000) 25 20 Lactic acid (0.5, 1.3%) PLA (2000) 25 20Ethyl heptanoate (0.5, 1.3%) PLA (2000) 25 20 Polyethylene glycol (0.5,1.3%) PLA (2000) 25 20 Polypropylene carbonate (0.5, 1.3%) PLA (2000) 2520 Polyvinyl pyrrolidone (0.5, 1.3%) PLA (2000) 25 20 Ethanol (0.5,1.3%) PLA (2000) 30 20 None PLA (2000) 20 20 PLG (5%) PLA (2000) 40 10None PLA (2000) 40 20 NonePolylactide:

Formulations containing risperidone at 5% and 10% by weight in 40%polylactide (IV=0.24 dL/g) and IV=0.36 dL/g) gave a fairly rapid burstof drug in vitro and the drug release slowed considerably such that lessthan 40% of the total drug was released in 15 days. The 20% risperidoneformulation was slightly better in that 50% of the drug was released in30 days, however, the viscosity of this highly drug-loaded formulationwas too high for injectability. A change to lower molecular weightpolylactide (MW=2000, IV=0.11 dL/g) and lower polymer concentrations(25%) gave much better in vitro release characteristics. A nearzero-order release profile was obtained and approximately 98% of thedrug was released in 34 days for this 20% risperidone formulation. Theinitial burst on Day 1 was 27 μg/mg formulation and the daily releasefrom Day 1 through Day 30 was 3 to 4 μg/mg. Additives such as lacticacid, ethanol, ethyl heptanoate, propylene carbonate, and polyethyleneglycol were added to the formulation at 0.5, 1.0 and 3.0% by weight inefforts to decrease the solubility of risperidone inN-methyl-2-pyrrolidone or the water that diffused into the polymermatrix and subsequently reduce the burst effect even further. None ofthe additives tested had any effect on the initial drug release.However, an increase in the low IV polymer concentration from 25% to 40%showed a significant lowering of the initial burst from the 27 μg/mgobserved earlier to 18.8 μg/mg formulation.

PLG:

The poly(lactide-co-glycolide) formulations of risperidone in which thecopolymer had a high lactide content (85/15 poly(lactide-co-glycolide)and 65/35 PLG) gave in vitro release profiles similar to that for thepolylactide homopolymer with the fairly high initial burst and lowlevels of sustained release thereafter. The release profiles wereobtained with the 58/50 poly(lactide-co-glycolide) materials. Nearzero-order release of risperidone was obtained with all formulations andabout 78 to about 90% of the drug was released in 30 days. Whereasrelease from the other polymer formulations slowed after several days,the 50/50 polymers appeared to swell after about seven days and releaselarger and more constant amounts of risperidone. This effect is shownfor the 50/50 poly(lactide-co-glycolide) with IV=0.35 dL/g and for thesame polymer with the lower IV=0.19 dL/g. The near zero-order releaserates were obtained with all of the 50/50 poly(lactide-co-glycolide)formulations. These included formulations with 5, 10, and 20% drug andthose with 25, 30, and 40% polymer. The differences observed were thatthe formulations with higher drug loadings and lower polymerconcentrations tended to give higher burst levels.

Poly(Lactide-Co-Caprolactone):

The risperidone formulations containing poly(lactide-co-caprolactone) inN-methyl-2-pyrrolidone were similar to those obtained with thepolylactide homopolymer in that a fairly high initial burst of drug wasobserved and the release rate slowed considerably after the first week.This effect is shown for the 10% risperidone formulations and for the20% risperidone formulations. Although the burst effect was reduced forthe same formulations containing 40% polymer, the viscosity of theseformulations was too high for suitable injectability.

ATRIGEL® Delivery System with Ethyl Lactate as the Biocompatible SolventSolubility Limits:

Risperidone was soluble in ethyl lactate up to concentrations of 7.5% byweight. However, when polymer was added to the formulations 5% byweight, the risperidone formulations remained as solutions. In contrastto the results obtained with N-methyl-2-pyrrolidone, the order ofaddition of polymer and risperidone to ethyl lactate had no effect. Allpolymer formulations with 5% by weight drug load were solutions. Higherdrug loadings in the ATRIGEL® system were suspensions.

In Vitro Release:

As with the N-methyl-2-pyrrolidone studies, a wide-variety of polymers,polymer molecular weights, polymer concentrations, drug loadings, andadditives were used to prepare formulations with ethyl lactate as thesolvent. Initial efforts were aimed at obtaining formulations that weresolutions and which could be injected easily. Later efforts focused uponreducing the initial burst of drug from the polymer formulations. Theformulations prepared with ethyl lactate and evaluated are given inTable 42.

TABLE 42 Polymer Formulations Using Ethyl Lactate Polymer % Polymer %Drug Load Additives 50/50 PLG (0.35) 40 5.0 None 50/50 PLG (0.35) 40 7.5None 50/50 PLG (0.35) 40 10.0 None 50/50 PLG (0.35) 20 5.0 None 50/50PLG (0.35) 20 7.5 None 50/50 PLG (0.35) 20 10.0 None 50/50 PLG (0.35) 405.0 None 50/50 PLG (0.19) 40 7.5 None 50/50 PLG (0.19) 40 10.0 None50/50 PLG (0.19) 30 5.0 None 50/50 PLG (0.19) 30 7.5 None 50/50 PLG(0.19) 30 10.0 None 50/50 PLG (0.19) 20 5.0 None 50/50 PLG (0.19) 20 7.5None 50/50 PLG (0.19) 20 10.0 None 50/50 PLG (0.19) 30 10.0 None 85/15PLG (0.24) 30 20.0 None 85/15 PLG (0.24) 30 10.0 None 65/35 PLG (0.23)30 20.0 None 65/35 PLG (0.23) 30 10.0 None 50/50 PLG (0.52) 30 20.0 None85/15 PLG (0.69) 30 10.0 None 85/15 PLG (0.69) 30 20.0 None 65/35 PLG(0.69) 30 10.0 None 65/35 PLG (0.69) 30 20.0 None 50/50 PLG (0.35) 405.0 Lactic acid (0.5%) 50/50 PLG (0.35) 40 5.0 Lactic acid (1.0%) 50/50PLG (0.35) 40 5.0 Lactic acid (3.0%) 50/50 PLG (0.35) 40 10.0 Lacticacid (0.5%) 50/50 PLG (0.35) 40 10.0 Lactic acid (1.0%) 50/50 PLG (0.35)40 10.0 Lactic acid (3.0%) 50/50 PLG (0.35) 40 5.0 Ethyl heptanoate(0.5%) 50/50 PLG (0.35) 40 5.0 Ethyl heptanoate (1.0%) 50/50 PLG (0.35)40 5.0 Ethyl heptanoate (3.0%) 50/50 PLG (0.35) 40 10.0 Ethyl heptanoate(0.5%) 50/50 PLG (0.35) 40 10.0 Ethyl heptanoate (1.0%) 50/50 PLG (0.35)40 10.0 Ethyl heptanoate (3.0%) 75/25 PLC (0.74) 40 5.0 None 75/25 PLC(0.74) 40 7.5 None 75/25 PLC (0.74) 40 10.0 None 75/25 PLC (0.74) 30 5.0None 75/25 PLC (0.74) 30 7.5 None 75/25 PLC (0.74) 30 10.0 None 75/25PLC (0.74) 20 5.0 None 75/25 PLC (0.74) 20 7.5 None 75/25 PLC (0.74) 2010.0 None 75/25 PLC (0.74) 27 5.0 None 75/25 PLC (0.74) 30 20.0 None PLA(0.24) 40 5.0 None PLA (0.24) 40 7.5 None PLA (0.24) 40 10.0 None PLA(0.37) 40 5.0 None PLA (0.37) 40 7.5 None PLA (0.37) 40 10.0 None PLA(2000) 25 10 None PLA (2000) 25 20 None PLA (2000) 40 5.0 Lactic acid(0.5%) PLA (2000) 40 5.0 Lactic acid (1.0%) PLA (2000) 40 5.0 Lacticacid (3.0%) PLA (2000) 40 10.0 Lactic acid (0.5%) PLA (2000) 40 10.0Lactic acid (1.0%) PLA (2000) 40 10.0 Lactic acid (3.0%) PLA (2000) 405.0 Ethyl heptanoate (0.5%) PLA (2000) 40 5.0 Ethyl heptanoate (1.0%)PLA (2000) 40 5.0 Ethyl heptanoate (3.0%) PLA (2000) 40 10.0 Ethylheptanoate (0.5%) PLA (2000) 40 10.0 Ethyl heptanoate (1.0%) PLA (2000)40 10.0 Ethyl heptanoate (3.0%) PLA (2000) 40 10.0 None PLA (2000) 4010.0 PLA (0.32) 5% PLA (2000) 40 10.0 PLA (0.32) 10% PLA (2000) 40 10.0PLA (0.32) 15% PLA (2000) 55 10.0 NonePolylactide:

The first formulations containing polylactide with IV=0.24 dL/g andIV=0.37 dL/g similar to those obtained with N-methyl-2-pyrrolidone werenot encouraging. Neither of these formulations released over 20% of thedrug load in the seven days of evaluation and the release rates were notconstant. A change to a low molecular weight polylactide (MW=2000,IV=0.11 dL/g) gave much better results in that the release rates weresustained at fairly constant levels for 25 days. However, the initialburst of drug was still relatively high (30-38 μg/mg of formulation). Anincrease in the polymer concentration reduced the initial burst to 10μg/mg, and gave nearly constant release of risperidone out to 19 days.The relatively low burst effect is probably due to the higher polymerconcentration and the higher drug loading, both changes which decreasethe solubility of risperidone in the ethyl lactate solvent. The lacticacid and ethyl heptanoate additives had no effect upon the initialrelease of drug.

PLG:

Initial trials with risperidone in poly(lactide-co-glycolide)formulations used 5% drug loadings, a 50/50 PLG, and a polymerconcentration of 40% by weight. In these formulations, the drug was insolution. However, at 5° C., the risperidone precipitated to formsuspensions. A lowering of the polymer concentration to 20% enabled thedrug to remain in solution even at 5° C. Any formulation withrisperidone levels greater than 5% were suspensions. As expected, theformulations with 20% polymer concentration gave high initial bursts ofdrug followed by fairly constant release for about 14 days. After thattime, the release rates dropped to low levels. The formulations with 40%polymer concentration gave less of an initial burst than the 20% polymerformulations, but the initial release was still relatively high with15-20% of the drug being released in 24 hours. The remainder of the drugwas the released at a fairly constant rate for 30 days. Thepoly(lactide-co-glycolide) polymers with higher lactide content(65/35-85/15) did not reduce the burst as did slow of the formulationswith lactic acid and ethyl heptanoate.

Poly(Lactide-Co-Caprolactone):

The release characteristics of risperidone in these polymers was similarto those obtained for the poly(lactide-co-glycolide) materials. With a50/50 poly(lactide-co-caprolactone) at 40% polymer concentration andvarious loads of risperidone, the initial burst of drug was about 13 toabout 20% followed by fairly constant release thereafter. However, thecumulative percent of drug released in 30 days was about 75%, a valueless than that obtained with the poly(lactide-co-glycolide) materials.An increase in the molecular weight of the poly(lactide-co-caprolactone)polymer from an IV=0.63 dL/g to IV=0.74 dL/g and an increase in thelactide content to 75/25 reduced the initial burst and the cumulativerelease after 30 days. The 40% polymer formulations were viscous.Therefore the polymer concentration was reduced to 20%. As with theother polymers, the lower concentration of polymer gave formulationswith large initial burst of drug and relatively fast release of theremaining drug with some formulations releasing 90% of the drug in 20days.

In Vivo Release:

First Dog Study

Based upon an evaluation of all the formulations prepared during thefirst two months of the program, four formulations (EXAMPLES 6-1, 6-2,6-3, and 6-4) were selected for the first study in dogs. Formulationsthat gave a variety of release rates were selected as no in vitro to invivo correlation was available at that time. All of the formulationscontinue to release risperidone out to 30 days with some giving more ofa burst effect than others. The formulations ware also selected toprovide two that were solutions in ethyl lactate and two that weresuspensions in N-methyl-2-pyrrolidone. The effect of solvent type aswell as drug solubility in the solvents was to be evaluated In addition,the formulations consisted of three different polymers with the fourthbeing the same as one of the others but with a lower molecular weight.Polymer compatibility and possibly degradation rate were also to beevaluated.

The results of the apomorphine challenge in dogs tested with the fourformulations are given in Tables 43-44.

TABLE 43 Formulation (mg eq/gr Body Weight Dose Group formulation) DogNo. (kg) (mg · kg, im) A risperidone 1 14.5 2.6 (50)/PLC/Ethyl 2 14.42.6 Lactate, 18 3 14.5 2.6 gauge needle (750 mg form, im) B risperidone4 11.8 2.1 (50)/PLG/Ethyl 5 10.3 2.4 Lactate, 18 6 10.5 2.4 gauge needle(500 mg form, im) C risperidone 7 11.6 2.2 (100)/PLC/NMP, 8 13.3 1.9 18gauge needle 9 10.9 2.3 (250 mg form, im) D risperidone 10 13.7 2.7(100)/PLG/NMP, 11 12.3 3.0 18 gauge needle 12 14.4 2.6 (250 mg form, im)

TABLE 44 Dose mg/kg A B C D Dog # 1 Dog # 2 Dog # 3 Dog # 4 Dog # 5 Dog# 6 Dog # 7 Dog # 8 Dog # 9 Dog # 10 Dog # 11 Dog # 12 2.6 2.6 (im) 2.62.1 2.4 (im) 2.4 2.2 1.9 (im) 2.3 2.7 3.0 (im) 2.6  1hour + + + + + + + + + + + +  5 hour + + + + + + + + + + + +  1day + + + + + + + + + + + +  4 day + + + + + + + + + + + +  7 day − −− + + + + + + + + + 11 day − − − − − − + − + + − + 14 day stop − + − +− + + + + 18 day stop − + − − − − 21 day − − − stop 25 day stop

These data show that the formulations with ethyl lactate protected thedogs for 4-7 days. The formulations in N-methyl-2-pyrrolidone showedactivity up to 14 days. The results of the pharmacokinetic analysis ofthe blood samples are given in Tables 45-48 and shown in FIGS. 25-28,respectively.

TABLE 45 Risperidone (50)/Poly(DL-lactide-co-caprolactone)/EthylLactate, 18 gauge needle (750 mg form, im) R64766 ng/ml R76477 ng/ml Dog# 1 Dog # 2 Dog # 3 Mean Mean Day Time 2.6 (Im) 2.6 (Im) 2.6 (±SD) Dog #1 Dog # 2 Dog # 3 (±SD) 1  0 hour ND ND ND ND ND ND  1 hour  1404+ 1108+  639+ 1050 (385.7)   496+  131+ 83.5+ 234 (220.0)  5 hour   322+  281+  286+ 296 (22.4)  1502+  849+  560+ 970 (482.6) 2  24 hour  14.2+ 12.3+ 14.7+ 14 (1.3)   829+  581+  395+ 602 (217.7) 5  96 hour  3.1+ NDND  1 (1.8)  67.4+ 40.4+ 28.4+ 45 (20.0) 8 158 hour ND ND ND ND ND ND 12264 hour NS NS NS NS NS NS “+” means protection against apomorphinereduced emesis

TABLE 46 Risperidone (50)/Poly(DL-lactide-co-glycolide)/Ethyl Lactate,18 gauge needle (500 mg form, im) R64766 ng/ml R76477 ng/ml Dog # 4 Dog# 5 Dog # 6 Mean Mean Day Time 2.1 (Im) 2.4 (Im) 2.4 (±SD) Dog # 4 Dog #5 Dog # 6 (±SD) 1  0 hour ND ND ND ND ND ND  1 hour  615+  315+  382+437 (157.5)  333+  101+  177+ 204 (118.3)  5 hour  115+  144+ 58.3+ 106943.60  854+  455+  512+ 607 (215.8) 2  24 hour 13.3+ 23.8+ 15.7+ 18(5.5)   289+  250+  218+ 252 (35.6)  5  96 hour  6.2+  2.9+  4.4+ 5(1.7) 29.7+ 21.1+ 21.2+ 24 (4.9)  8 158 hour ND ND ND 13.8+ 10.8+  9.0+11 (2.4)  12 264 hour ND ND ND ND ND ND 15  36 hour ND ND ND ND ND ND“+” means protection against apomorphine reduced emesis

TABLE 47 Risperidone(100)/Poly(DL-lactide-co-caprolactone)/N-methyl-2-pyrrolidone, 18 gaugeneedle (250 mg form, im) R64766 ng/ml R76477 ng/ml Dog # 7 Dog # 8 Dog #9 Mean Mean Day Time 2.62 1.9 (Im) 2.3 (Im) (±SD) Dog # 7 Dog # 8 Dog #9 (±SD) 1  0 hour ND ND ND ND ND ND  1 hour  111+  108+ 92.7+ 104 (9.8) 48.8+ 40.3+ 36.7+ 43 (5.4)   5 hour 60.7+ 39.0+ 39.1+ 46 (12.5)  187+ 113+  100+ 133 (46.9)  2  24 hour 13.8+ 15.2+ 12.9+ 14 (1.2)   220+ 174+  130+ 175 (45.0)  5  96 hour  4.4+ ND  2.7+ 2 (2.2) 71.5+ 33.1+37.7+ 47 (21.0) 8 158 hour  2.2+ ND  3.6+ 2 (1.8) 29.1+  9.3+ 21.7+ 20(10.0) 12 264 hour ND ND ND 15.4+ ND 13.2+ 10 (8.3)  15 336 hour ND NDND 20.0+ ND 10.3+ 10 (10.0) 19 432 hour ND ND ND  7.9   ND  7.3+ 5 (4.4)22 504 hour ND ND ND ND ND ND “+” means protection against apomorphinereduced emesis

TABLE 48 Risperidone(100)/Poly(DL-lactide-co-glycolide)/N-methyl-2-pyrrolidone, 18 gaugeneedle (250 mg form, im) R64766 ng/ml R76477 ng/ml Dog # 10 Dog # 11 Dog# 12 Mean Mean Day Time 2.7 (Im) 3.0 (Im) 2.6 (Im) (±SD) Dog # 10 Dog #11 Dog # 12 (±SD) 1  0 hour ND ND ND ND ND ND  1 hour  170+ 96.8+  162+143 (40.2)  62.4+ 34.4+ 57.1+ 51 (14.9)  5 hour 64.9+ 39.2+ 43.1+ 49(13.9)  152+ 98.5+  155+ 139 (35.2)  2  24 hour 17.5+ 13.2+ 13.4+ 15(2.4)   146+  113+  169+ 143 (28.1)  5  96 hour  9.2+  6.3+  9.1+ 8(1.6) 80.3+ 77.0+ 75.9+ 78 (2.3)  8 158 hour  6.0+  2.7+  5.3+ 5 (1.7)30.4+ 36.4+ 37.2+ 35 (3.7)  12 264 hour  3.8+  2.1  ND 1 (1.9) 18.8+10.4    7.6+ 12 (5.8)  15 336 hour  2.3+ ND ND 3 (0.4) 11.4+ 10.0+  5.7+9 (3.0) 19 432 hour ND ND ND ND  6.1   ND 2 (3.5) “+” means protectionagainst apomorphine reduced emesis

These data show that the two formulations with ethyl lactate gave a highinitial burst of drug at approximately 800-1400 ng/mL and the plasmalevels of dug dropped fairly quickly within one week to where the sum ofrisperidone and its metabolite were below the minimum level of 10-45mg/mL needed for activity. The two formulations withN-methyl-2-pyrrolidone gave much less of a burst with plasma levels forthe drug and metabolite at approximately 200 ng/mL. The plasma levelswere also sustained above the minimum for about 15 to about 19 daysshowing a much more constant release for these two formulations.

Both the pharmacological (apomorphine challenge) and the pharmacokineticdata correlate fairly well with the in vitro daily release rates for thefour formulations. If the in vitro daily release rate in terms of μg ofrisperidone, released/mg of formulation is multiplied by the quantity(mg) of formulation injected into the dogs, a risperidone release (mg)in the dogs on a daily basis can be predicted. The data suggests theminimum daily dose of risperidone needed in dogs for a biologicalresponse is about 0.6 mg. Both of the formulations with ethyl lactateshow a large amount of drug calculated to be released in the first day.EXAMPLE 6-1, the poly(lactide-co-caprolactone) polymer formulation, alsoshows that the quantity of drug released falls below 0.6 mg about Day 4.The biological response obtained with this formulation was for about 4-5days. The other ethyl lactate formulation (EXAMPLE 6-4) containing thepoly(lactide-co-glycolide) polymer maintains the 0.6 mg level out to Day6. The levels of risperidone fall slightly below this value through Day16. Biological responses to this formulation were observed through Day 8with one dog responding at Day 15. The two formulations withN-methyl-2-pyrrolidone maintain the level of risperidone much longer.EXAMPLE 6-2 with poly(lactide-co-caprolactone) maintains the 0.6 mgrisperidone level to Day 13. The biological response was obtained forall three dogs at Day 8 with 2 animals responding to Day 15. Thepoly(lactide-co-glycolide) formulation with N-methyl-2-pyrrolidone wascalculated to maintain the 0.6 mg level to Day 20. Biological responsewas observed at Day 15. This particular polymer degrades quickly in vivoand may have fragmented and released the drug faster than predictedbased upon in vitro data.

Second Dog Study

The data from the first study in dogs indicated that formulations withsignificant reductions in the initial burst of drug would be desired asthe maximum tolerated blood level for risperidone and its metabolite wasestimated as 75 ng/mL. Above this level, safety concerns abouthypertension and other side effects would be major considerations. Ofthe many formulations tested in vitro, it was found that two appeared tomeet the requirement for a low initial burst of risperidone followed byconstant release far 38 days. These were the low molecular weight(MW=2000, IV=0.11 dL/g) polylactide formulation with a highconcentration of polymer (55%) and the 50/50 poly(lactide-co-glycolide)formulation with an IV=0.35 dL/g. These two formulations were projectedto meet the target range of plasma levels for risperidone by a series ofcalculations based upon the initial in vitro release of drug and theplasma level at one hour from the first four formulations tested indogs. Thus, if the percent of drug released in 24 hours in vitro ismultiplied by the quantity of drug in the formulation, a value for thequantity of drug released initially is obtained. Table 49 gives thesevalues for the first four formulations tested in dogs and the two newformulations proposed for additional studies. Sixteen (16) of theseinitial in vitro release values for the first four formulations testedin dogs are plotted versus the plasma levels at one hour for risperidoneand its 9-hydroxyl metabolite and a curve can be used to obtain acorrelation of in vitro to in vivo drug release. When the initial invitro values for the two new formulations are inserted into the secondorder polynomial, the estimated plasma levels at one hour are 63.9 ng/mLfor the polylactide formulation and 31.1 ng/mL for thepoly(lactide-co-glycolide) formulation. These plasma levels fit wellwithin the targeted range of 15-75 ng/mL.

TABLE 49 Calculated Values for Initial Quantity of Risperidone Releasedfrom formulations Tested in Dogs Quantity of Drug (mg) NumberDescription Released in 24 hours EXAMPLE 6-1 75/25 PLC (IV = 0.76 10.13dL/g) in ethyl lactate 5% risperidone EXAMPLE 6-2 50/50 PLC (IV = 0.633.63 dL/g) in NMP 10% risperidone EXAMPLE 6-3 50/50 PLC (IV = 0.19 4.13dL/g) in NMP 10% risperidone EXAMPLE 6-4 50/50 PLC (IV = 0.35 10.75dL/g) in ethyl lactate 5% risperidone EXAMPLE 6-5 50/50 PLC (IV = 0.351.25 dL/g) in NMP 10% risperidone EXAMPLE 6-6 55% PLA (MW = 2000; 2.50IV = 0.11 dL/g) in ethyl lactate, 10% risperidone

The two new formulations were prepared and both the pharmacologicalresponse (apomorphine challenge) and pharmacokinetic analysis ofrisperidone plasma levels were to be evaluated. The results weredisappointing in that effects were seen for about two weeks for theapomorphine challenge as noted in Tables 50-51. Also, generalobservation of the animals suggested that a high burst of drug was stillbeing obtained as the animals were heavily sedated during the first fourdays of the trial. A severe local inflammation resulting in abscesseswas noted for the formulation containing ethyl lactate. In addition, theviscosities of the test formulations were judged to be too high forpractical use.

TABLE 50 Formulation (mg eq/gr Body Weight Dose Group formulation) DogNo. (kg) (mg · kg, im) C 50/50 PLC (IV = Dog # 4 12.7 2.5 0.35 dL/g) inNMP Dog # 5 10.6 2.6 10% risperidone Dog # 6 11.7 2.4 D 55% PLA (MW =Dog # 13 9.6 2.8 2000; IV = Dog # 14 12.8 2.5 0.11 dL/g) in Dog # 15 8.02.5 ethyl lactate, 10% risperidone

TABLE 51 Dose mg/kg C D Dog # Dog # Dog # Dog # Dog # Dog # 4 5 (im) 613 14 (im) 15  1 hour + + + + + +  5 hour + + + + + +  1 day + + + + + + 4 day + + + + + +  7 day + + + + + + 11 day + + − + + + 14 day − + −− + + 18 day − + − − − + 21 day − + − − − − 25 day stop stop

The results from the second dog study were unexpected. No localinflammatory response had been observed previously with the ethyllactate solvent. The response in this study may have been caused by somedegradation of the solvent itself or the combination with the lowmolecular weight polylactide polymer. The large burst effect noted bythe sedation of the dogs (but not confirmed by pharmacokinetic analyses)was also unexpected for these two formulations and prompted aninvestigation. It was discovered that the method of preparation of theformulations affected the initial release of drug. The release profileswere generated from formulations in which the risperidone, solvent andpolymer were mixed together and allowed to equilibrate 24 hours beforein vitro testing. The formulation with poly(lactide-co-glycolide) wasactually prepared by mixing the risperidone in N-methyl-2-pyrrolidoneand adding polymer with stirring until the polymer had dissolved. Thepolylactide formulation with ethyl lactate was prepared by dissolvingthe polymer in ethyl lactate and adding risperidone with stirring toobtain adequate mixing. However, because of potential storage stabilityproblems, the two formulations tested in dogs were prepared bydissolving each polymer in the appropriate solvent and placing eachpolymer solution in a syringe. The risperidone in powder form wasweighed into two separate syringes. The four syringes were coupled to apolymer solution syringes and mixed the two materials immediately beforeuse. When the two formulations produced by this method were tested invitro, the initial release of drug was increased over that shown by thesame formulations produced by earlier method. Both formulations preparedby this syringe-mixing method gave almost identical in vitro releaserates with the initial burst of drug being about 12% instead of theprevious about 5 to about 10% used in the calculations to predict drugplasma levels. At the 72% initial burst, the plasma levels in the dogswould have been predicted to be greater than 200 ng/mL.

Implant Retrieval Study in Rats:

In efforts to reduce the initial burst of drug and to obtain somecorrelation of in vitro to in vivo release, a study was conducted inrats in which formulations were injected into rats and the solid polymerimplant retrieved at various times for analysis of residual polymer. Thefour formulations tested are given in Table 52.

TABLE 52 Polymer Solvent Drug Loading Additive PLA (MW = 2000; NMP 20%None IV = 0.11 dL/g), 25% 50/50 PLG (IV = NMP 10% None 0.35 dL/g) 30%50/50 PLG (IV = EL  5% None 0.35 dL/g) 40% 50/50 PLG (IV = EL 10% EthylHeptanoate 0.35 dL/g) 30% 3%

The percent drug released based upon residual drug in the implants wasdetermined for each of the formulations. Although the data are highlyvariable because of the difficulty in retrieving the implants, they showthat the formulation with 5% risperidone in ethyl lactate gave a highinitial release of drug. The data also show that the initial burst withthis formulation can be reduced by the use of the hydrophobic additive,ethyl heptanoate. The data also show that the initial burst is reducedeven more with the polylactide and poly(lactide-co-glycolide)formulations in N-methyl-2-pyrrolidone. It should be noted that all ofthe formulations gave higher drug release in vivo than in the laboratorytests.

Stability and Sterilization Studies:

Because of the difficulties in obtaining formulations with the desiredin vivo release characteristics, the stability program with thedifferent formulations was limited to short-term observations. Theformulations containing risperidone in N-methyl-2-pyrrolidone weresuspensions which were not physically stable as they settled out at alldrug loads evaluated in a short time of about two days. In addition, therisperidone/N-methyl-2-pyrrolidone formulations showed color instabilityproblems upon storage at temperatures above 5° C. as they tended todarken with time.

The risperidone/ethyl lactate formulations were more stable than thosewith N-methyl-2-pyrrolidone. The formulations with 5% drug weresolutions but tended to form white crystals at 5° C. storage condition.When warmed back to room temperature, the crystals re-dissolved.Formulations with drug levels above 5% were suspensions which were alsophysically unstable as they settled out with time. However, the ethyllactate formulations gave better color stability at 5° C. and roomtemperature as there was no color change in the formulations after onemonth at room temperature.

Eight formulations were prepared for gamma irradiation sterilization aswere solutions of risperidone (5%) in ethyl lactate andN-methyl-2-pyrrolidone and risperidone alone. The dose level was 30 to33 KGy for each of the samples.

Upon visual inspection, the syringes and glass vials containing thesterilized risperidone/polymer formulations with N-methyl-2-pyrrolidonewere amber to brown in color in comparison to non-sterilized controlswhich were a yellow color. There was a yellow/beige color observed inthe drug itself after sterilization in both the glass vials andsyringes. The 5% risperidone formulation in ethyl lactate was yellowcompared to its colorless control sample and the 5% risperidoneformulation in N-methyl-2-pyrrolidone was brown in comparison to theyellow color observed in the non-radiated controls.

Analysis of the risperidone in the formulations was performed by theHigh Performance Liquid Chromatography method described above. Syringesand glass vials obtained from the gamma radiation testing were analyzedwith the control formulations. The results are reported in Table 53. Theisocratic as well as the gradient High Performance Liquid Chromatographymethods used to analyze these samples failed to detect any additionalcompounds. The cause for the color change observed in the syringes andglass vials which were gamma irradiated has not been determined.

TABLE 53 Analysis for Risperidone After Gamma Radiation of FormulationsGamma Gamma Radiation Radiation Risperidone Glass Vials SyringesConcentration Risperidone Risperidone Sample (mg/g) (mg/g) (mg/g) 5%Risperidone/Ethyl 48.0 48.0 53.4 Lactate/40% (50/50)PLG 20%Risperidone/NMP/ 204.1 188.3 209.7 25% PLA 10% Risperidone/NMP/ 192.379.8 90.8 25% (50/50)PLG 10% Risperidone/NMP/ 107.5 84.4 103.2 30% PLG5% Risperidone/EL/ 49.8 47.8 47.5 20% PLG 10% Risperidone/NMP/ 114.696.3 88 25% PLC 5% Risperidone/EL/ 52.5 57.4 55.4 20% PLG 5%Risperidone/EL/ 53.1 49.3 51.8 27% PLC

A second series of irradiation experiments were also conducted usingdifferent levels of irradiation from 5 KGy to 31 KGy to determine theeffect of dose level upon stability. In these experiments, the 50/50poly(lactide-co-glycolide) polymers with IV=0.35 dL/g and IV=0.49 dL/gwere dissolved in N-methyl-2-pyrrolidone at 30% concentration. Thesewere loaded into gamma-irradiation polypropylene syringes and capped.Risperidone powder was also loaded into gamma-resistant polypropylenesyringes and cap. The materials were exposed to irradiation at fourdifferent levels: 5.8 KGy, 18.3 KGy, 27.9 KGy, and 31 KGy. Generalobservations were that the polymer solution in N-methyl-2-pyrrolidonegradually changed from clear to slightly yellow as the level ofirradiation increased. On addition, risperidone which was initiallywhite turned beige at the lowest level of irradiation and the colordarkened as the level of irradiation increased.

CONCLUSIONS

The results showed that risperidone could be incorporated into theATRIGEL® Drug Delivery System and released at controlled rates forsustained periods of time. The formulations in which risperidone wassuspended in the liquid polymer delivery system appeared to give thelowest initial drug burst and the most sustained release over time.These formulations were the 50/50 poly(lactide-co-glycolide) inN-methyl-2-pyrrolidone and the low molecular weight polylactide in ethyllactate. Of the two solvents evaluated, N-methyl-2-pyrrolidone gave thebest release characteristics. In general, the use of low molecularweight polymers at relatively high polymer concentrations tended toreduce the initial burst and sustain drug delivery. However, none of theformulations tested in animals were able to reduce the initial plasmaconcentration of risperidone to safe levels and none were able tosustain a pharmacological effect past about two weeks.

All patents and publications referenced or mentioned herein areindicative of the levels of skill of those skilled in the art to whichthe invention pertains, and each such referenced patent or publicationis hereby incorporated by reference to the same extent as if it had beenincorporated by reference in its entirety individually or set forthherein in its entirety. Applicants reserve the right to physicallyincorporate into this specification any and all materials andinformation from any such cited patents or publications.

The specific methods and compositions described herein arerepresentative of preferred embodiments and are exemplary and notintended as limitations on the scope of the invention. Other objects,aspects, and embodiments will occur to those skilled in the art uponconsideration of this specification, and are encompassed within thespirit of the invention as defined by the scope of the claims. It willbe readily apparent to one skilled in the art that varying substitutionsand modifications may be made to the invention disclosed herein withoutdeparting from the scope and spirit of the invention. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, or limitation or limitations, which is notspecifically disclosed herein as essential. The methods and processesillustratively described herein suitably may be practiced in differingorders of steps, and that they are not necessarily restricted to theorders of steps indicated herein or in the claims.

What is claimed is:
 1. An injectable, flowable composition comprising(a) about 15 wt % risperidone base in (b) about 45 wt % of an 80/20poly(DL-lactide-co-glycolide) biodegradable thermoplastic polyester witha terminal carboxy group having an average molecular weight of about10,000 Daltons to about 50,000 Daltons; and (c) about 55 wt % ofN-methyl-2-pyrrolidone.
 2. The composition of claim 1, wherein theflowable composition is subcutaneously injectable.
 3. The composition ofclaim 1, wherein the flowable composition transforms into a solidimplant in situ after contact with water, body fluid, or other aqueousmedium.
 4. The composition of claim 1, wherein the flowable compositionproduces maximum plasma concentration (C_(max)) levels of risperidonewithin about 6 hours after injection into a patient.
 5. The compositionof claim 1, wherein the flowable composition produces maximum plasmaconcentration (C_(max)) levels of risperidone within about 2 hours afterinjection into a patient.
 6. The composition of claim 1, wherein thebiodegradable thermoplastic polyester has an average molecular weight ofabout 15,000 Daltons to about 40,000 Daltons.
 7. The composition ofclaim 1, wherein the biodegradable thermoplastic polyester has apolydispersity index of about 1.4 to about 2.0.